Process for the preparation of 9beta,10beta steroids

ABSTRACT

THE PRESENT INVENTION IS DIRECTED TO A PROCESS FOR THE COMPLETE CHEMICAL SYNTHESIS OF STEROIDS HAVING THE 9B, 10A-CONFIGURATION FROM THE NATURAL STERIOIDS POSSESSING THE 9A, 10B-CONFIGURATION INCLUDING INTERMEDIATES IN THIS SYNTHESIS. THE STEROIDS WITH THE 9B,10A-CONFIGURATION ARE USEFUL AS ANABOLIC AGENTS, ANTI-ANDROGENIC AGENTS, PROGESTATIONAL AGENTS AND AS SALT-RETAINING AGENTS.

United States Patent ABSTRACT OF THE DISCLOSURE The present invention isdirected to a process for the complete chemical synthesis of steroidshaving the 9B, wot-configuration from the natural steroids possessingthe 9a,l0,8-configuration including intermediates in this synthesis. Thesteroidswith the 9fi,10a-configuration are useful as anabolic agents,anti-androgenic agents, progestational agents and as salt-retainingagents.

CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisionalapplication of our pending application Ser. No. 499,094, filed Oct. 20,1965,

now U.S. Pat. No. 3,574,761, which in turn is a con- .tinuation-in-partapplication of our earlier filed U.S.

application Ser. No. 400,206, filed Sept. 29, 1964, now U.S. Pat. No.3,412,107.

BACKGROUND OF THE INVENTION This invention relates to novel chemicalintermediates and processes useful in the preparation of steroids.Natural steroids possess a 9fl,l0a-stereochemical configuration.Steroidal compounds possessing the unnatural 9,8, wot-configurationrepresent a pharmaceutically valuable class of compounds which, eventhough numerous members are known in the art, cannot be obtained bytotally classical chemical means. In fact, the only known methods forobtaining steroids possessing the unnatural 95,10- configuration involveat least one photochemical reaction. Such photochemical reactionsinvolve irradiation with ultraviolet light of strong intensity forlongperiods of time and, in comparison with purely chemical reactions, arevery inetficient and give only small yields.

It is an object of the present invention to provide intermediates andprocesses which enable the preparation of 913,10a steroids without thenecessity of proceeding through a photochemical reaction. It is also anobject of this invention to provide novel intermediates and processeswhich will enable the further exploration of steroids having theunnatural 9/3,10a-configuration. It is also an object of this inventionto provide novel 95,1004-St61'0id8.

The novel intermediates and processes of this invention are valuable andprovide a new synthetic route completely of a classical chemical nature,i.e. involving no photochemical reaction, for converting steroids havingthe normal configuration into steroidal compounds possessing theunnatural 9,8,10ot-COIlfigl1l3ti0ll.

In one aspect, the novel intermediates and processes of this inventionenable the preparation of 9p,l0a-steroids of the androstane series ofthe formula wherein R is, individually, selected from the groupconsisting of hydroxy and lower alkanoyloxy; R is individually, hydrogenor lower alkyl and R and R taken together, are selected from the groupconsisting of (l7B-OH, 17u-lower alkanoic acid lactone) and oxo; R isselected from the group consisting of hydrogen, lower alkyl, hydroxy andlower alkanoyloxy; Y is selected from the group consisting of hydrogenand lower alkyl and X is a substituent in the 6- or 7-position selectedfrom the group consisting of hydrogen, lower alkyl, lower alkylthio,lower alkanoylthio and halogen.

Compounds of Formula I are useful as anabolic agents.

Other 9B,10a-androstanes, the preparation of which is enabled by theintermediates and processes of this invention, are of the formulae H3OR1 lower alkenyl wherein R R Y and X have the same meaning as above.Compounds of Formula III are useful as progestational agents andcompounds of Formula II are useful as antiandrogenic agents.

In another embodiment of this invention, the novel compounds andintermediates provided by this inventron 3 enable the preparation of9p,l0a-steroids of the 175- pregnane series of the formula OJVIVJCompounds of Formula IV are useful as progestational agents.

Other 9fi,10cz-t6I'OidS of the l7/8-pregnane series, preparable from thenovel compounds and process of this invention, are of the formulawherein R';, R Y and X have the same meaning as above.

Compounds of Formula V are useful as salt-retaining agents, i.e. areuseful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both straight andbranched chain saturated hydrocarbon groups, such as methyl, ethyl,propyl, isopropyl and the like. Similarly, the term lower alkanoylcomprehends groups such as acetyl and the like, and the term loweralkanoyloxy comprehends groups e.g. formyloxy, acetoxy and the like. Inthe same manner, the term lower alkenyl comprehends groups such as vinyland the like, and the term lower alkynyl comprehends groups such asethinyl and the like. Halogen comprehends all four halogens, i.e.iodine, bromine, chlorine and fluorine.

The expression (l7fi-OH, l7a-lower alkanoic acid lactone) refers to aconfiguration on the C-17 carbon atom illustrated as follows:

wherein W is lower alkylene, e.g.

polymethylenes such as ethylene, propylene or the like.

With respect to substituents in the 6- and 7-position, preferredcompounds are those having hydrogen or lower alkyl in 6- or 7-position,and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of9,8,la-androstanes of Formulae IIII and of 9fi,l0a-l7fl-pregnanes ofFormulae IVV which comprises the hydrogenation ofdesA-androst-9-en-5-ones or of desA-17B-pregn-9-en-5-ones to95,10fl-desA-androstan-- ones or 9 3,l0/3-desA-l7fl-pregnan-5-ones,respectively, followed by condensation with a lower alkyl vinyl ketonewith methyl or ethyl vinyl ketone preferred (as well as substitutestherefor such as l-tertiary amino-3-butanone, l-tertiaryamino-3-pentanone and quaternary ammonium salts thereof),1-Q-butan-3-one, l-Q-butan-3-one lower alkyltene ketal, l-Q-butan-3-ol,esterified 1-Q-butan-3-ol, l-Q-butan-3-ol ether, 1,3-dichlorobut-2-ene,1,3-dichloropent-Z-ene, 1-pentan-3-one, 1-Q-pentan-3-one lower alkyleneketal, l-Q-pentan-3-ol, esterified 1-Q-pentan-3-ol or 1- Q-pentan-3-olether, which condensation yields the desired 9/3,10a-steriods. Thesymbols Q is bromine, chlorine or iodine, with the former two beingpreferred. This invention also provides a number of different methodsfor the preparation of said desA-androst-9-en-5-one or desA- 178-pregn-9-en-5-one starting materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst-4-ene or3-oxo-l7,8-pregn-4-ene series is subjected to an oxidative ring Openingof the A-ring yielding a 5-oxo-3,5-seco-A- norandrostan-3-oic acid or a5-oxo-3,5-seco-A-nor-17B- pregnan-B-oic acid, which 3-oic acid can thenbe converted to a mixture of a lOa-desA-androstan-S-One and a 10;?-desA-androstan-S-one or a mixture of a l0a-desA-l7flpregnan-S-one and a10 3-desA-pregnan-5-one. The conversion of the 3-oic acid to thedesA-compound can be effected either by pyrolysis of a salt of said3-oic acid or via the enol lactone, i.e. a 4-oxoandrost-5-en-3-one or a4-0xcv 17,8-pregn-5-en-3-one, which upon reaction with a Grignardreagent gives an aldol, which in turn can be converted into the desireddesA-compound. The desA-compound can then be converted into the startingmaterial desA-androst- 9-en-5-one or desA-17,8-pregn-9-en-5-one via atwo-step sequence of halogenation and dehydrohalogenation.

In another embodiment of this invention, desA-androst- 9-en-5-one ordesA-l7,8-pregn-9-en-5-one starting materials can be prepared fromll-hydroxy steroids of the 3- oxo-androst-4-ene or 3-OXO-l7B-prcgn-4-eneseries. This can be effected in a variety of ways. In one approach, anll-hydroxy group of a steroid of the 3-oxo-androst-4-ene or3-oxo-l7fi-pregn-4-ene series is converted into a leaving group, forexample, a sulfonic acid ester or carboxylic acid ester. Oxidative ringopening of the A-ring of the thus formed ll-(esterifiedhydroxy)-containin g compound yields the corresponding ll-(esterifiedhydroxy)-5-ox0-3, 5-seco-A-norandrostan-3-oic acid or ll-(esterified hydroxy)-5-0xo-3,5-seco-A-nor-17B-pregnan-3-oic acid which upon pyrolysisof a salt of said 3-oic acid yields the desired desA-androst-9-en-5-0neor desA-17,8-pregn-9-en-5- one starting material.

A further apporach involves formation of anll-hydroxy-desA-androstan-S-one or ll-hydroxy desA 17/3- pregnan-S-onefrom an ll-hydroxy steroid of the 3-0X0- androst-4-ene or3-oxo-l7B-pregn-4-ene series via an oxidative ring opening of the A-ringof said ll-hydroxy steroid which yields anll-hydroxy-5-oxo-A-nor-3,S-seco-androstan-3-oic acid 3,1l-lactone or anll-hydroxy-5-oxo-3,5- seco-l7B-pregnan-3-oic acid 3,ll-lactone which, inturn is converted into a salt of the corresponding keto acid which saltupon pyrolysis gives the ll-hydroxy-desA- androstan-S-one or1l-hydroxy-desA-l7B-pregnan-5 one. Esterification of the ll-hydroxymoiety of the so-obtained compound with an acid moiety yields anll-(esterified hydroxy)-desA-androstan-5-one or an ll-(esterifiedhydroxy)-desA-l7 3-pregnan-5-one which upon elimination of the leavinggroup (i.e., the esterified hydroxy moiety) gives the desireddesA-androst-9-en-5-one or desA-l7;8- pregn-9-en-5-one startingmaterial. Though, in-the above: reaction sequence either Ila-OH orllfi-OH starting material steroids can be used, it is preferred to useIla-- OH starting materials.

As will be appreciated from the above discussion, neither the specificreaction steps nor the reaction sequences of this invention involve anymodification of substituents found in the 16- and/or l7-pmitionQfJlE.-sta.tt

ing material natural steroids. However, in order to obtain unnatural9,6,10wster0ids of Formulae I-V, it is necessary or desirable to protectcertain of the 16- and/or 17- substituents against one or more of thereaction steps involved. It is also convenient to initially protect sucha substituent in the starting material natural steroid and maintain thesubstituent in its protected form throughout the entire reactionsequence, regenerating the desired substituent only when the steroid ofFormulae I-V possessing the unnatural 9/3,10a-configuration is obtained.On the other hand, it is sometimes convenient to insert a protectinggroup only before a certain reaction step or sequence of reaction steps.Said protecting group can then be maintained until the final reactionstep or can be split oif at some intermediate stage. The protectinggroups can be inserted and split off by means know per se. Thedesirability of having protecting groups present will be furtherdiscussed below when the specific reaction steps are discussed indetail. The various substituents which are susceptible to beingprotected are exemplified by the 16-hydroxy group in a compound of anyof Formulas I-V, the 17/8-hydroxy group in a compound of any of FormulasI III, the l7a-hydroxy or 20-ox0 group in a compound of any of FormulasIV-V, the 21-hydroxy group of a compound of Formula V or the 17-oxogroup of a compound of Formula I.

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e.,by reaction with a lower alkanediol, to yield a 17-lower alkylene dioxyor 20-lower alkylene dioxy compound, i.e., a 17-ketal or a ZO-ketal.

The 16-hydroxy, Nor-hydroxy, 17/3-hydroxy or 21- hydroXy moieties can beprotected by esterification and/or etherification of the hydroxy group.Any available acid which will form an ester that can subsequently behydrolyzed to regenerate the hydroxy group is suitable. Exemplary acidsuseful for this purpose are lower alkanoic acids, e.g. acetic acid,caproic acid, benzoic acid, phosphoric acid and lower alkanedicarboxylic acids, e.g. succinic acid. Also, protection for the16a-hydroxy, 17ahydroxy, or 21-hydroxy substituent can be effected byforming the lower alkyl ortho ester thereof, i.e. 16ot,17aor17a,21-lower alkyl ortho esters. A suitable ether protecting group is,for example, the tetrahydropyranyl ether. Others are arylmethyl etherssuch as, for example, the benzyl, benzhydryl and trityl ethers, ora-lower alkoxylower alkyl ethers, for example, the methoxymethyl, orallylic ethers.

' In compounds containing the dihydroxyacetone side chain at C-l7 (forexample, compounds of Formula V wherein R is hydroxy), the side chain at0-17 can be protected by forming the 17,20; 20,2l-bis-methylenedioxygroup or by forming a 17,21-acetal or ketal group, or by forming a17,21-diester. The 17,21-acetal or ketal and 17,2l-diester hinder theZO-ketone group and minimize the possibility of its participating inunwanted side reactions. On the other hand, the 17,20;21,21-bis-methylenedioxy derivatives actually convert the ketone to anon-reactive derivative. When both a l6a-hydroxy and Not-hydroxysubstituent are present, these groups-can be protected via formation ofa 16u,17a-acetal or ketal. The various protecting groups mentioned abovecan be removed by means known per se, for example, by mild acidhydrolysis.

In compounds wherein there is present neither a 170thydroxy nor2l-hydroxy substituent but there is present a 20-oxo group, the 20-oxogroup can be protected via reduction to the corresponding carbinol(hydroxy) group. Thus, for example, the 17-acetyl side chain can beprotected via conversion to a 17-(a-hydroxyethyl)-side chain.Regeneration of the 17-acetyl side chain can be simply effected viaconventional oxidation means, for example, via oxidation with chromiumtrioxide'in an organic solvent such as glacial acetic acid. Similarly incompounds containing a 17-oxo, this group can be protected by reductionto the corresponding carbinol (hydroxy) group. Thus, the -17-oxo groupcan be reduced to a 17,8-OH, l7ot-H moiety, from which, when desired,the 17-oxo moiety can be regenerated by oxidation, as described above.Furthermore, a ZO-hydroxy or 17,6-hydroxy group, can itself be protectedby esterification, for example, with a lower alkanoic acid such asacetic acid, caproic acid, or the like; or by etherification withmoieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl,or the like.

The 1611- or 17a,2l-acetals and ketals above discu sed can be formed byreacting 16a,l7a-bis-hydroxy or 17a,21-bis-hydroxy starting materialswith an aldehyde or a ketone; preferably it is done by reacting a simpleacetal or ketal (i.e. a lower alkylene glycol acetal or ketal of asuitable aldehyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanals of at least twocarbon atoms, such as paraldehyde, propanal and hexanal; di(loweralkyl)ketones, such as acetone, diethylketone, dibutylketone,methylethylketone, and methylisobutylketone; cycloalkanones, such ascyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (loweralkanals), such as cyclopentylcarboxaldehyde andcyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such ascyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkylketones, such as dicyclopentyl ketone, dicyclohexyl ketone andcyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones,such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenylketone, cyclopentyl o,p'dihydroxy-phenyl ketone and cyclohexyl m-tolylketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such ascyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-loweralkyl ketones, such as cyclopentyl benzyl ketone and cycloheXylphenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkylketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals,such as chloral hydrate, trifluoroacetaldehyde hemiacetal, andheptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as1,1,1-trifiuoroacetone; monocyclic carbocyclic aromatic aldehydes, suchas benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde andp-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g. o-anisaldehyde),di(lower alkoxy)benzaldehydes (e.g. veratraldehyde),hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes(e.g. m-tolualdehyde and oethylbenzaldehyde), di(loweralkyl)-benzaldehydes (e.g. o-p-dimethylbenzaldehyde); monocycliccarboxylic aromatic lower alkanals, such as phenylacetaldehyde,uphenylpropionaldehyde, ,B-phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy,hydroxy and lower alkyl cyano derivatives thereof; monocycliccarbocyclic aromatic ketones, such as acetophenone,a,a,a-trifluoroacetophenone, propionphenone, butyrophenone,valerophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenoneand p-chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones(e.g. panisyl methyl ketone); di-(lower alkoxy) phenyl lower alkylketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl loweralkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl loweralkyl ketones (o,p-xylyl) methyl ketone; benzophenone, and monoorbis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivativesthereof; monocyclic carbocyclic aromatic lower alkanones, such asl-phenyl-3- butanone and l-phenyl-4-pentanone, and aromaticallysubstituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the16a,17otor 17u,21-bis-hydroxy grouping form an acetal or ketal group ofthe formula wherein P is individually selected from the group consistingof hydrogen and lower alkyl; Q is individually selected from the groupconsisting of lower alkyl and aryl; and P and Q taken together are loweralkylene.

Ha'c

rnc

X (VI Thus, 95,10a-androstanes of Formula I can be prepared from9/3,10fi-desA-androstan-S-ones of the formula wherein R R R and X havethe same meaning as above.

Similarly, 9 8,10a-androstanes of Formula II can be preprepared from95,105 desA androstan 5 ones of Formula VIII and 9 3,10a-androstanes ofFormula III from 9 8,lOfi-desA-androstan-S-ones of Formula IX.

1 H3O I -1ower alkenyl (vrrr --lowet alkynyl wherein R R and X have thesame meaning as above.

8 Moreover, 95,10a-17fi-pregnanes of Formulae IV and V can be preparedfrom 9/3,10fl-desA-pregnan-5-ones of Formulae X and XI, respectively.

CH1R5 =0 Hacl wherein R R R and X have the same meaning as above.

The conversion of a 95,105-desA-compound of Formula VI to a 95,100;steroid of Formulae I-V (i.e., VII- 1, VIII- II, IX III, X IV,and XI- V)is effected by condensing the 9fl,l0B-desA-compound with acompoundselected from the group consisting of lower alkyl vinyl ketone(as well as substitutes therefor such as 1- tertiary amino-3-butanone,l-tertiary amino-3-pentan-one and quaternary ammonium salts thereof),1,3-dichlorobut 2 ene, 1,3-dichloropent 2 ene, 1-Q-butan-3-one, 1 Qbutan 3 one lower alkylene ketal, 1-Q-butan-3- ol, 1 Q -butan 3 olether, esterified 1-Q-butan-3-ol, l-Q-pentan-3-one, 1 Q pentan 3 onelower alkylene ketal, 1-Q-pentan-3-ol, 1 Q pentan 3 o1 ether oresterified 1-Q-penta-3-ol. Q is bromo, chloro or iodo, with the formertwo being preferred. Methyl vinyl ketone and l-tertiary amino 3 butanoneare the preferred reagents, and the former is especially preferred.Prior to the condensation it is desirable to protect the 20-keto grouppresent in compounds of Formulae X and XI, then it is not necessary toprotect 16a,17a or 21-hydroxy groups which are present, but groupsprotecting these moieties can be retained through the condensationreaction.

The above indicated substitutes for lower alkyl vinyl ketones arecompounds wherein the vinyl moiety is replaced by a moiety of theformula wherein each R is lower alkyl or taken together both Rs arelower alkylene, oxa-lower alkylene or aza-lower alkylene. Such moietiesare, for example, dimethylamino, diethylamino, pyrrolidino, piperidino,morpholino, or the like. The quaternary ammonium salts thereof areformed via the utilization of conventional quaternizing agents, forexample, lower alkyl or phenyl-lower alkyl (especially benzyl) halides,mesylates or tosylates.

When a lower alkyl vinyl ketone or substitute therefor, 1-Q-butane-3-one0f l-Q-pentan 3 one is used as the reaction partner for thecondensation, ring closure to ring A (containing a 3-oxo moiety) of thedesired 96,100;- steroid of Formulae I-V occurs simultaneously with thecondensation. However, when 1,3-dichlorobut-2-ene, 1,3- dichloropent 2ene, l-Q-butan 3 one lower alkylene ketal, 1 Q butan-3-o1,l-Q-butan-3-ol ether, esterified 1-Q-butan-3-ol, l-Q-pentan 3 one loweralkylene ketal, l-Q-pentan-3-ol, 1-Q-pentan-3-ol ether, or esterified 1-Q-pentan 3 01 is used as the reaction partner a subsequent step togenerate the 3-oxo moiety is required. When l-Q-butan-S-ol or1-Q-pentan-3-ol is used as the reaction partner, the x0 moiety can begenerated by oxidation and for this purpose, it is suitable to useoxidation means known per se, for example, chromic acid, chromiumtrioxide in acetic acid or the like. When esterified or etherified1-Q-butan-3-ol or esterified or etherified l-Q-pentan-S-ol is used asthe reaction partner, hydrolysis of the esterified or etherified hydroxygroup should be effected prior to oxidation. Suitable ester formingmoieties are, for example, carboxylic acid, e.g. lower alkanoic acidsuch as acetic acid, benzoic acid, and the like; and hydrolysis of thereaction products obtained by reacting such 1-Q-butan-3 -ol orl-Q-pentan-3-ol esters is suitably conducted by alkaline hydrolysis,e.g., via the use of an aqueous alkali metal hydroxide such as aqueoussodium hydroxide. Suitable ethers are, for example, lower alkyl ethers,i.e. 3-methoxy, 3-ethoxy or the like; and these are suitably hydrolyzedby acid hydrolysis, e.g. via the use of an aqueous mineral acid such ashydrochloric acid, sulfuric acid or the like. When a l-Q-butan- 3-onelower alkylene ketal or a 1-Q-pentan-3-one lower alkylene ketal is usedas the reaction partner, mild acid hydrolysis of the ketal moietyresults in generation of the 3-oxo moiety. Finally, when1,3-dichlorobut-3-ene or 1,3 dichloropent 3 ene is used as the reactionpartner, the 3-oxo moiety can be generated by treatment with aconcentrated mineral acid, preferably a strong acid such as hydrochloricacid or sulfuric acid. It should be noted, that 1,3-dichlorobut 2 eneand 1,3-dichloropent-2-ene may be used as reaction partners withcompounds of Formulae X and XI, but not with the l7a-lower alkyl,alkenyl or alkynyl compounds of Formulae VIII-IX. As will be apparent,when a reaction partner based on butane (i.e. having a four carbon atomskeleton) is utilized a compound of Formulae I-V wherein Y is hydrogenis obtained. Similarly, when a reaction partner based on pentane isutilized a compound of Formulae I-V wherein Y is methyl is obtained.

In addition to the preparation of compounds of Formulae I-V fromcompounds of Formulae VI-XI by the use of the above mentioned reactionpartners, it is also possible by the procedures of this invention toprepare compounds of Formulae I-V which, in the A-ring, in addition tocontaining an unsaturation between the 4- and 5-positions also containan unsaturation between the 1- and 2-positions. Such 1,4-diene productscorresponding to the compounds of Formulae I-V can be prepared fromcompounds of Formulae VIXI by condensation of the latter with a reactionpartner selected from the group consisting of ethinyl methyl ketone andethinyl ethyl ketone (as well as substitutes therefor such asfl-tertiary amino-vinyl methyl or ethyl ketone, quaternary ammoniumsalts thereof, and ,B-lower al'koxy-vinyl methyl or ethyl ketone).Condensation to prepare such as 1,4-diene product corresponding to thecompounds of Fromulae I-V is effected under the same conditions as isthe condensation to prepare a compound of Formulae IV. The so-obtained1,4-dienes are useful in the same way as the correspondingly substituted4 ene compounds of Formulae I-V.

The condensation is suitably effected at, below or above roomtemperature. For example, at the reflux temperature of the reactionmedium or at ice temperature (0 C.) or below. Moreover, the condensationis suitably effected in an organic medium. Preferably the solvent is alower alkanol, such as methanol, isopropanol, tertbutanol, ethanol, oranother non-ketonic organic solvent, such as an ether, e.g. dioxane,diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g. benzene,toluene, xylene,

organic acid, such as acetic acid, or the like. Lower alkanols are thepreferred solvents. It is suitable to catalyze the condensation, andthis can be effected via use of a catalyst such as an alkali metal loweralkoxide, for example sodium ethoxide, potassium t-butoxide, sodiumtamylate, or the like, alkali metal hydroxide such as so dium, lithiumor potassium hydroxide, a quaternary ammonium hydroxide, for example, abenzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethylammonium hydroxide, para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl ketone, or for methylor ethyl ethinyl ketone, the condensation should be effected underalkaline conditions. As indicated above, among such substitutes arel-tertiary amino 3 butanone, l-tertiary amino 3 pentanone andfi-tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary aminogroups are dilower alkylamino groups such as dimethylamino,diethylamino, pyrrolidino, piperidino, morpholino, or the like.Preferred quaternary ammonium salts of such tertiary amino groups are,for example, those formed from lower alkyl halides such as methyliodide. An exemplary fi-lower alkoxy vinyl methyl or ethyl ketone is,B-methoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation of desA-androst 9 en 5ones or desA-pregn-9-en-5- ones to 9fl,10,8-desA-androstan 5 ones ofFormulae VII-IX or to 9,8,10,8-desA-pregnan 5 ones of Formulae X-XI.Thus, 9,8,10fl-desA-androstan-S-ones of Formula VII can be prepared viahydrogenation of desA-androst- 9-en-5-ones of the formulae wherein R R Rand X have the same meaning as above.

Also, 95,IOfl-desA-pregnan-S-ones of Formulae X and XI can be preparedby hydrogenation of desA-pregn-9-en-5- ones of the formulae CH2R5 XVIwherein R' R R and X have the same meaning as above.

Prior to hydrogenation, the C- keto group in compounds of Formulae XVand XVI or C-l7 keto group in compounds of Formula XII should beprotected either by conversion to the corresponding carbinol or byketalization as described above. The hydrogenation can, however, beeffected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting ahydrogen atom in each of the 9- and lO-positions, can alsosimultaneously effect hydrogenation of other groups in the molecule. Forexample, the C-20-keto group can be hydrogenated to the correspondingcarbinol or the C-17 lower alkenyl group in compounds of Formula XIII orthe C-l7 lower alkynyl group in compounds of Formula XIV can behydrogenated to the corresponding C-l7-lower alkyl compounds. Compoundsof Formulae VIII and IX can, in turn, be prepared from compounds ofFormula VII wherein R and R together are oxo via reaction with a loweralkenyl or lower alkynyl Grignard reagent, with prior protection of the5-keto group, for example, by forming S-ketals without concurrentblocking of the 17-keto group. In the same manner compounds of FormulaeXIII and XIV can be formed from compounds of Formula XII wherein R and Rtaken together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of Formulae XII-XIV and ofdesA-pregn-9-en-5-ones of Formulae XV-XVI is one of the main features ofthis invention. It is effected by catalytic hydrogenation, suitablyusing a precious metal catalyst. Suitable precious metal catalysts arepalladium, platinum, ruthenium, and rhodium, the latter two beingespecially preferred. It is particularly advantageous to us rhodium, forexample, rhodium on charcoal (or carbon powder, carbon black, or thelike) or rhodium on alumina. In contrast to what would be expected, ithas been found that such a catalytic hydrogenation of a compound ofFormulae XII- XVI gives a substantial yield of a compound of FormulaeVI-XI. In fact, it has been found that such catalytic hydrogenationgives a major proportion of a compound of the Formula VI-XI. Thiscatalytic hydrogenation is suitably effected in an inert organicsolvent, for example, a lower alkanol such as methanol or ethanol, anether such as dioxane or diglyme, a hydrocarbon such as cyclohexane,hexane, or the like. Lower alkanols are preferred solvents. Moreover, itis suitably conducted in the presence of an acidic or basic catalyst,for example, an alkali metal or alkaline earth metal hydroxide such assodium hydroxide or the like, or a mineral acid, for example, ahydrohalic acid, such as hydrochloric acid, or the like, or an organicacid such as a lower alkanoic acid, for example, acetic acid. Thereaction can be conducted at, above or below room temperature, forexample, from about -5 C. to about 100 C. However, it is preferablyconducted at a temperature between about 0 C. and about C.

As described above, the desA-androst-9-ene-5-ones ordesA-l7B-pregn-9-en-5-ones of Formulae XII-XVI can be prepared fromnatural steroids by a variety of methods. Thus, in one embodiment ofthis invention said desA- androst-9-en-5-ones ordesA-l7fl-pregn-9-en-5-ones can be prepared from steroids of the3-oxo-androst-4-ene or 3- oxo-l7fi-pregn-4-ene series by a reactionsequence which involves as a first step an oxidative ring opening ofring A of the natural steroid. For this oxidative ring opening there canbe used as starting materials, natural steroids of the3-oxo-androst-4-ene, or 3-oxo-17/3-pregn-4-ene series of the formula:

(XVII) wherein X is a substituent in the 6-position selected from thegroup consisting of hydrogen, lower alkyl, lower alkylthio and loweralkanoylthio or a substituent in the 7-position selected from the groupconsisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthioand halogen, and Z represents the carbon and hydrogen atoms necessary tocomplete the steroid D-ring, as well as the atoms in the substituents inthe 16- and 17-positions as defined in Formulae I, IV, and V above.

The oxidative ring opening of a natural steroid of Formula XVII yields a5-oxo-3,S-seco-A-norandrostan-3-oic acid or a5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula (XVIII) wherein Xand Z have the same meaning as above.

The oxidative ring opening of the compound of Formula XVII can beperformed by a variety of methods. In a preferred embodiment it iseffected by ozonolysis. The ozonolysis is suitably carried out in anorganic solvent, for example, acetic acid, ethyl acetate, methanol,chloroform, methylene chloride, or the like, or a mixture of two or moreof such solvents such as ethyl acetate/acetic acid, ethylacetate/methylene chloride, or the like. Moreover, the ozonolysis isadvantageously conducted at below room temperature. Thus, it ispreferably conducted at a temperature between about C. and about 25 C.The resulting ozonides can be decomposed by conventional means, forexample, by treatment with water, hydrogen peroxide in water, aceticacid or ethyl acetate, or the like. The oxidative ring opening of acompound of Formula XVII to a compound of Formula XVIII can also beeffected by other oxidation means, for example, by treatment withhydrogen peroxide. It should be noted that an oxidative ring opening byeither ozonolysis or by treatment with hydrogen peroxide, does notrequire protection of any of the substituents at C-l6 or C-l7. However,as stated above, it may be desirable to protect these substituentsagainst some subsequent reaction in the total reaction sequence beingpracticed. On the other hand, the oxidative ring opening can also beeffected by oxidation with chromium trioxide or via treatment withsodium periodate and potassium permanganate in potassium carbonatesolution and if these oxidation means are used, it is necessary toprotect any secondary hydroxy groups which might be present such as a16,175- or 2l-hydroxy group; preferably, for the purpose of thisreaction, with non-aromatic protecting groups.

wherein in 'Form ulae' XIX and XX, X and Z have the same meaning asabove. p

The compounds of Formula XIX are 10u-desA-androstan- 5- ones orla-desA-pregnan-5-ones, depending on the meaning of Z, and the compoundsof Formula XX are l0/s-desA-androstan -ones or fl-desA-pregnan-5-ones.The conversion of a compound of Formula XVIII into the compounds ofFormulae XIX and XX is effected by pyrolysis. In effecting thepyrolysis, it is desirable to convert the 3-oic acid of Formula XVIIIinto a corresponding metal salt, for example, an alkali metal salt suchas the sodium or lithium salt. This conversion to a metal salt can beeffected prior to pyrolysis, e.g., by treating the acid Withsodiumhydroxide or in situ during the course of the pyrolysis, e.g., by fusingthe 3-oic acid with a mixture of sodium acetate and potassium acetate.The pyrolysis can be conductedat atmospheric pressure or in a vacuum.One preferable embodiment is to conduct the pyrolysis in a vacuum, at atemperature from about 200 C. to about 350 C. in the presence of aportion acceptor, e.g. an alkali metal or alkaline earth metal salt of aweak organic acid, for example, potassium acetate, sodium acetate,sodium phenyl-acetate, sodium bicarbonate, or the like; es-

pecially-preferred is a vacuum of from about .001 to about .5 mm. Hg.Accordingly, it is advantageous to conduct the pyrolysis under alkalineconditions, i.e. at a pH greater than 7. The pyrolysis can be effectedin solution or by fusion. An especially preferred method of effectingthe pyrolysis is by fusion of an alkali metal salt of a weak acid, forexample, an organic carboxylic acid such as a lower alkanoic acid or aphenyl-lower alkanoic acid such a s phe nyl-acetic acid. Another methodof effecting the pyrolysis is to heat, preferably at atmosphericpressure, a

solutionof an alkali metal salt, such as the sodium or lithium salt, ofa 3-oic acid of Formula XVIII in a basic organic solvent. The basicorganic solvent should, of course, be one which is in the liquid stateat the temperature at which the pyrolysis is effected. Thus, thepyrolysis can be effected at a temperature up to the boiling point ofthe basic organic solvent being used. Suitable basic organic solventsare, for example, nitrogen containing organic solvents such aspiperidine, pyridine, isoquinoline, quinoline, triethanolamine, or thelike. When utilizing this approach using a basic organic solvent it issuitable to heat totemperature between about 200 C. and about 300? C.,and preferably between about 230 C. and about 260 C. A preferred basicorganic solvent for wherein X and Z have the same meaning as above.

The compounds of Formula XIX can be prepared from compounds of FormulaXIX A in the same manner that compounds of Formula XIX are prepared fromcompounds of Formula XVII, i.e. by oxidative ring opening of the A-ringof a compound of Formula XIX A followed by elimination of the residue ofthe A-ring, to yield a compound of Formula XIX. The oxidative ringopening of the compound of XIX A can be performed by ozonolysis asdescribed above for the conversion of a compound of Formula XVII to acompound of Formula XVII. Such ozonolysis of a compound of Formula XIX Ayields a compound of the formula (XIX-A) (XIX-B) wherein X and Z havethe same meaning as above, and A is carboxy or formyl.

A compound of Formula XIX-B can then be converted to a compound ofFormula XIX. This removal of the residue of the A-ring, i.e.decarboxylation and deformylation, can be effected by heating in anacidic or basic medium. It is preferred to heat to the refluxtemperature of the medium which is preferably an inert organic solventsuch as a lower alkanol, e.g. ethanol, dioxane, ether or the like. Thedecarboxylation and deformylation yields mainly a compound of FormulaXIX, but also a minor yield of the corresponding lOB-isomer of FormulaXX.

Compounds of Formula XIX can also be formed from a compound of FormulaXVIII via the formation of an enol-lactone of a compound of FormulaXVIII, i.e., via the formation of a 4-oxo-androst-5-en-3-one or a4-oxopregn-5-en-3-one of the formula:

wherein X and Z have the same meaning as above,

which can then reacted with a Grignard reagent, such as phenyl magnesiumbromide or phenyl lithium, to form the resulting aldol of, for example,the formula CeHs H (XXII) wherein X and Z have the same meaning asabove,

which, upon treatment with an alkali metal hydroxide, such as potassiumhydroxide, at an elevated temperature, for example, from about 200 C. toabout 240 C., is converted to the corresponding lOa-desA-androstan-S-oneor a-desA-pregnan-5-one of Formula XIX.

It should be noted that though the pyrolysis of a compound of FormulaXVIII yields both the 10,8-compounds of Formula XX and the wot-compoundsof Formula XIX, and though either of these isomers can be used in thesubsequent halogenation and dehydro-halogenation steps of this reactionsequence, it is sometimes preferable to convert the lOfl-compound ofFormula XX into the corresponding loot-compound of Formula XIX. Thisconversion can be effected by treating a 10B-desA-androstan- S-one orIOB-desA-pregnan-S-one of Formula XX with any base capable of producinga carbanion; for example, it is suitable to use an alkali metal loweralkoxide in an organic solvent such as a lower alkanol, for example,sodium ethoxide in an ethanol solution or sodium methoxide in a methanolsolution.

The above-discussed conversion via the alkali metal salt and pyrolysisof compounds of Formula XVIII to compounds of Formulas XIX and XX can beeffected without protection of any of the substituents which might bepresent at C-16 or C-17. However, if it is desired for either precedingor succeeding reaction steps of the total reaction sequence, theconversion of a compound of Formula XVIII to compounds of Formulas XIXand XX can be effected with protecting groups present on substituents inthe C-16 or C-17 position.

As stated above, the 10cc desA androstan-S-ones orIOu-desA-pregnan-S-Ones of Formula XIX or the 10pdesA-androstan-S-onesof 103 desA-pregnan-S-ones of Formula XX can be converted via a two-stepsequence of halogenation and dehydrohalogenation into the desiredstarting material desA-androst-9-en-5-one or desA-pregn- 9-en-5-one ofFormulas XII, XV, and XVI.

In a preferred embodiment a 10a-desA-androstan-5- one or aIOa-desA-pregnan-S-One of Formula XIX is subjected to the two-stepsequence of halogenation and dehydrohalogenation. Halogenation of acompound of Formula XIX or a compound of Formula XX yields a mixture ofcorresponding halogenated compounds including one of the formula XXIIIwherein X and Z have the same meaning as above, and

Hal is a halogen atom (preferably Br or Cl).

Dehydrohalogenation of a compound of Formula XXIII then yields a desiredstarting material of Formulas XII, XV and XVI. Keto group except for theS-keto group, may require protection prior to the halogenation. In thecase of compounds of Formulas XIX and XX containing the C-17dihydroxyacetone side chain, represented in Formula V wherein R ishydroxy, this protection can be effected by formation of the 17,20;20,21-bis-methylenedioxy derivative. In other cases wherein a C-17 0x0or C-20 oxo group is present, protection can be effected by reduction tothe corresponding carbinol either directly prior to the halogenationstep or prior to some other step in the reaction sequence leading to thecompounds of Formulas XIX and XX.

The halogenation can be effected with halogenating agents such asbromine, sulfuryl chloride, or the like. Bromination is especiallypreferred. The bromination is suitably effected by treatment withbromine at room temperature or below, preferably at ice temperature orbelow. Suitably it is conducted in an organic medium; for example, anorganic acid such as acetic acid; an ether such as an anhydrous ether,dioxane, tetrahydrofuran; a chlorinated organic solvent such asmethylene chloride, chloroform, carbon tetrachloride; or the like; withthe addition of hydrogen bromide as a catalyst. When effectinghalogenation with sulfuryl chloride, it is suitable to use the same typeof organic medium as when brominating; and suitable catalysts are, forexample, acetic acid, benzoyl peroxide, or the like.

The subsequent dehydrohalogenation of a compound of Formula XXIII ispreferably conducted under mild dehydrohalogenating conditions; forexample, by the use of an alkali metal carbonate (e.g. lithiumcarbonate) or an alkali metal halogenide (e.g. a lithium halide) in anorganic solvent such as a di-lower alkyl-formamide, or with an organicbase such as collidine, pyridine, or the like. The dehydrohalogenationis advantageously conducted at slightly elevated temperatures, forexample, from about 50 C. to about 150 C., preferably from about C. toabout C.

Separation of the desired product desA-androst-9-en-5- one ordesA-pregn-9-en-5-one of Formulas XII, XV and XVI can be effected byconventional means. As indicated above the halogenation procedure mayresult in halogenated by-products in addition to the desiredintermediate of Formula XXIII. Accordingly, the separation is preferablyeffected after first subjecting the reaction mixture to dehalogenatingconditions in order to dehalogenate the halogenated by-products formedby the halogenation procedure, but not dehalogenated by thedehydrohalogenation. Following such dehalogenation the reaction mixturecan then easily be separated by conventional means, for example, bycolumn chromatography, to yield the desired compound of Formulas XII,XV, XVI. An examplary dehalogenation means is treatment with zinc andsodium acetate in an acetic acid solution at an elevated temperature,for example, about 80 C.

In the case of compounds of Formulas XIX or XX which contain a halogenatom on a carbon atom directly adjacent to a keto group, it ispreferable to protect such a halogen atom against dehalogenation priorto subjecting the compound of Formulas XIX or XX to the two stepsequence of halogenation and dehydrohalogenation of this embodiment.Such a grouping, containing a halogen atom on a carbon atom directlyadjacent to a keto group, is illustrated in a compound of Formulas IV orV wherein R or R is halogen. Thus, if 10w or 10fi-desA-pregnan- S-one ofFormulas XIX or XX containing a 17ocor 21- halo substituent is to besubjected to the halogenationdehydrohalogenation sequence it isdesirable to first effect protection of the 17aor 2l-halo substituent.This protection can be effected, for example, by ketalization of the20-oxo group.

As stated above, the desired desA-androst-9-cn-5-0ne8 ordesA-pregn-9-en-5-ones smiling materials can also be prepared fromsteroids of the 3-oxo-androst-4-ene or 3- oxo-17fl-pregn-4 ene seriescontaining an ll-hydroxy substituent. In one embodiment an ll-hydroxysteroid of the formula l H I H /Vl X (XXIV) wherein X and Z have thesame meaning as above,

is reacted with an acid or a reactive derivative thereof to form aleaving group in the ll-position. By reactive derivative is meant, forexample, a halide, e.g. a chloride, an anhydride, or the like. Thougheither 11,8- or lloc-hYdIOXY starting materials can be used, it ispreferable to utilize a-hydroxy compounds of Formula XXIV as startingmaterials. Prior to the esterification reaction, it is preferable toprotect hydroxy groups present in the C-16, -17, or 0-21 position.Suitable acids for the esterification of the ll-hydroxy group, which canbe used to .form a leaving group in the ll-position are inorganic acidssuch as phosphoric acid, organic carboxylic acids such as anthraquinone,B-carboxylic acid or organic sulfonic acids, for example,toluene-sulfonic acids, especially p-toluene sulfonic acid, loweralkyl-sulfonic acids such as methane-sulfonic acid andnitrophenyl-sulfonic acids, especially p-nitrophenylsulfonic acid.Especially preferred as the leaving group in the ll-position is a loweralkylsulfonyloxy group such as the mesoxy group. However, when it isdesired to react a compound of Formula XXIV with a sulfonyloxy formingmoiety, then a compound of Formula XXIV having an Hot-configurationshould be used as a starting material. The above describedesterification of ll-hydroxy steroid starting materials of Formula XXIVyields compounds of the formula (XXV) wherein X and Z have the samemeaning as above, and

LO represents the leaving group.

LO T Ham I 1 J X xxvr wherein X, Z and LO have the same meaning asabove.

to The oxidative ring opening of the A-rmg of a compound so-formedcompound of Formula XXVI under the conditions described above for thepyrolysis of a compound of Formula XVIII to compounds of the FormulasXIX and XX directly yields the desired desA-androst-9-en-5-one ordesA-pregn-9-en-5-one of Formulas XII, XV, XVI. Thus, pyrolysis of acompound of Formula XXVI directly results in elimination of the leavinggroup in the ll-position as well as a splitting ofi of the residue ofring A attached to the 10-position. This procedure of starting from anll-hydroxy steroid (preferably lla-hydroxy) of Formula XXIV andproceeding through intermediates of Formulas XXV and XXVI to compoundsof Formulas XII, XV, XVI, represents a particularly elegant procedurefor preparing the latter compounds. An especially preferred method ofeffecting the pyrolysis of a salt of a 3-oic acid of Formula XXVI is themethod described above wherein the salt of the 3-oic acid is heated in aliquid basic organic solvent. Especially preferred solvents for thepyrolysis of a salt of a compound of Formula XXVI are triethanolamineand quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of acompound of Formula XXVI involves two separate chemical attacks; onebeing the elimination of the ll-leaving group and the other being thesplitting off of the A-ring residue. Instead of effecting these twoattacks simultaneously, as described above, it is also possible toeffect them sequentially by just prior to formation of the salt,effecting elimination of the leaving group of the compound of FormulaXXVI. This elimination yields a A -seco acid of the formula (XXVI-A)wherein X and Z have the same meaning as above.

The elimination can be effected by any conventional elimination means.It is suitably conducted under alkaline conditions in an anhydrousorganic solvent. Preferably, it is effected by heating, i.e. at atemperature between about room temperature and the reflux temperature ofthe reaction mixture. Thus, treatment of a compound of Formula XXVI witheither an inorganic or organic acid or base results in the formation ofthe desired compound of Formula XXVI-A. Preferably a weak base is used,for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid)with an alkali metal or an alkaline earth metal, for example, sodiumacetate, potassium acetate, or the like. As indicated, the eliminationis suitably conducted in an anhydrous organic solvent; suitable aresolvents such as dilower alkyl-formamides, e.g. dirnethylformamide,lower alkanoic acids, e.g. acetic acid, or the like. When a protonaccepting solvent, such as dimethylformamide, is used, it itself canserve as the base for the purpose of this elimination reaction; i.e. ifthe solvent is basic then the elimination can be conducted without theaddition of a separate basic material. Similarly, if the solvent isacidic, then the elimination can be conducted without the addition of aseparate acidic material.

After the elimination is effected the A -seco acid product of FormulaXXVI-A can then be converted to a salt, for example, an alkali metalsalt, and the so-formed salt pyrolyzcd according to the conditionsdescribed above for the pyrolysis of a compound of Formula XXVI tocompounds of Formulas XII, XV and XVI.

After the above-described ll-leaving group elimination and A-ringresidue splitting, conducted either simultaneously or sequentially, thedesired desA-9-en-5-one compounds of Formulas XII, XV and XVI can beisolated by conventional means. However, it has been found particularlysuitable with compounds of Formulas XV and XVI to isolate by forming thedisemicarbazone of the pyrolysis product and then regenerating therefromthe desired 5,20- dione of Formulas XV or XVI, or if the 20-oxo grouphas been protected, for example, by reduction to a 20- hydroxy moiety,by forming the semicarba'zone at the position and then regeneratingtherefrom the desired 5- one compound.

In yet another embodiment of this invention starting material ll-hydroxysteroids of Formula XXIV can be directly subjected to an oxidative ringopenings of the A- ring by ozonolysis or treatment with hydroxideperoxide, as described above for the oxidative ring opening of theA-ring of a compound of Formula XVII to a compound of Formula XVIII.This oxidative ring opening of the A-ring of a compound of Formula XXIVyields an 11- hydroxy 5 oxo 3,5 seco-A-norandrostan-S-oic acid 3,11lactone or an 11 hydroxy 3 oxo-3,5-seco-A- norpregnan-3-oic acid3,11-lactone of the formula (XXVII) wherein X and Z have the samemeaning as above.

Treatment of the 3,1I-lactone of Formula XXVII with an alkali metalhydroxide such as sodium hydroxide gives the salt of the same keto acid.Without isolation, this salt can then be subjected to pyrolysis yieldinga mixture of an 11 hydroxy a desA-androstan-5-one and an 11 hydroxy10fi-desA-androstan-5-0ne or a mixture of an 11hydroxy-l0a-desA-pregnan-5-one and anll-hydroxy-IOfi-desA-pregnan-S-one, as illustrated below:

wherein in Formulas XXVIII and XXIX, X and Z have the same meaning asabove.

This pyrolysis of an alkali metal salt derived from a compound ofFormula XXVII can be effected under the same conditions as describedabove for the pyrolysis of a compound of Formula XVIII to compounds ofthe Formulae XIX and XX. Though either the 10,8-compound of FormulaXXVIII or the wet-compound of Formula XXIX can be subjected to thesubsequent steps of this reaction sequence, it is suitable to utilizethe IOB-compound of Formula XXVIII. Conversion of the wet-compound ofFormula XXIX to the IOB-compound of Formula XXVIII can be effected underthe same conditions as described above for the conversion of thecompound of Formula XX to a compound of Formula XIX.

In the next step of this reaction sequence, the ll-hydroxy compound ofFormula XXVIII or of Formula XXIX can be subjected to esterificationwhereby to convert the ll-hydroxy group to a leaving group in the IIposition. This esterification can be effected with the same acids oracid derivatives and in the same manner as described above for theesterification of a compound of 20 Formula XXIV to a compound of FormulaXXV. As in that instance, it is also preferred in the present instanceto form a mesoxy leaving group in the ll-position, though, of course,other leaving groups as described above are useful for the instantpurpose. There is thus obtained a compound of the formula (XXX) whereinX, Z and LO have the same meanings as above.

The leaving group can then be eliminated from the 11- position of acompound of Formula XXX resulting in a direct formation of adesA-androst-9-en-5-one or a desA- pregn-9-en-5-one of Formulae XII, XV,XVI. This elimination can be effected by any conventional eliminationmeans. It is suitably conducted under alkaline conditions in ananhydrous organic solvent. Preferably, it is effected by heating, i.e.at a temperature 'between about room temperature and the refluxtemperature of the reaction mixture. Thus, treatment of a compound ofFormula XXX with either an inorganic or organic base results in theformation of the desired compound of Formulae XII, XV, XVI. Preferably aweak base is used, for example, a salt of a carboxylic acid (e.g. alower alkanoic acid) with an alkali metal or an alkaline earth metal,for example, sodium acetate, potassium acetate, or the like. Asindicated, the elimination is suitably conducted in an anhydrous organicsolvent; suitable are solvents such as dilower alkyl-formamides, e.g.dimethyl formamide, lower alkanoic acids, eg acetic acid, or the like.When a proton accepting solvent, such as dimethyl formamide, is used, ititself can serve as the base for the purpose of this eliminationreaction; i.e. if the solvent is basic then the elimination can beconducted without the addition of a separate basic material.

In another aspect, compound of Formula XXX can be prepared fromcompounds of the formula (XXX-A) wherein X, Z and LO have the samemeanings as above. The compounds of Formula XXX-A can be prepared fromcorresponding ll-hydroxy compounds by esterification as described abovefor the preparation of compounds of Formula XXV from compounds offormula XXIV. The compounds of Formula XXX can be prepared fromcompounds of Formula XXXA in the same manner that compounds of FormulaXXX are prepared from compounds of Formula XXV, i.e. by oxidative ringopening of the A-ring of a compound of Formula XXX-A followed byelimination of the residue of the A-ring to yield a compound of FormulaXXX. The oxidative ring opening of the compounds of Formula XXX-A can beperformed by ozonolysis as described above for conversion of a compoundof Formula XXV to a compound of HaC X (XXX-B) wherein X, Z and LO havethe same meaning as above.

A compound of Formula XXX-B can then be converted to a compound ofFormula XXX. This removal of the residue of the A-ring, i.e.decarboxylation, can be effected as described above for the conversionof a compound of Formula XIX-B to a compound of Formula XIX.

The compounds of Formulae I-V preparable by the methods of thisinvention are not only pharmaceutically useful compounds as describedabove, but also are themselves useful as intermediates for other9fi3,10oz-St6r0ids; for example, compounds wherein X is hydrogen orlower alkyl can be modified so as to introduce unsaturation between C-6and C-7. This can be effected by dehydrogenation means, for example, byhalogenation followed by dehydrohalogenation or by means of2,3-dichloro-5,6- dicyanobenzoquinone, according to known methods. Thus,for example, a 95,10u-progesterone of Formula IV wherein X is hydrogenor lower alkyl can be converted to a 95,10u-pregna-4,6-dien-3,20-dione.

A further embodiment of this invention comprises the preparation of9,8,10a-steroids of formulae I-V containing an ll-hydroxy substituent.This can be effected by utilizing an 1l-hydroxy-IOa-desA-androstan-S-Oneor 11- hydroxy-10u-desA-pregnan-5-one of Formula XXIX or an1l-hydroxy-10'B-desA-androstan-5-one or ll-hydroxy-IOfi-desA-pregnan-S-one of Formula XXVIII as the starting materials. Itis preferred in this embodiment to use the 10fl-isomers of FormulaXXVIII as starting materials. As a first step in this 11-hydroxy groupof the compound of formulae XXVIII or XXIX should be protected. This issuitably effected by esterification, preferably with a carboxylic acid,for example, a lower alkanoic acid such as acetic acid, benzoic acid, orthe like. Conversion of the so-obtained ll-esterified hydroxy compoundthen yields an ll-(esterified hydroxy)-desA-androst-9-en-5-one (i.e. acompound of Formula XII containing an ll-esteritied hydroxy moiety) oran ll-esterified hydroxy-desA- pregn-9-en-5-one (i.e. a compound ofFormulae XV- XVI containing an Ila-esterified hydroxy moiety). Thisconversion can be effected by halogenation followed bydehydrohalogenation, as described above for the conversion of a compoundof Formulae XIX or XX to a compound of Formulae XII, XV or XVI.Catalytic hydrogenation of the so-obtained compound of the formulawherein X' and Z have the same meaning as above, and E0 is an esterifiedhydroxy group as described above in this paragraph,

yields an ll-esterified hydroxy-desA-9/3,IOB-androstan-S- one orll-esterified hydroxy-desA-9fl,10,8-pregnan-5-one, of the formula HaCXXX I wherein X, Z and E0 have the same meaning as above.

This hydrogenation can be conducted in the same manner as describedabove for the hydrogenation of a compound of Formulae XII-XVI to acompound of Formulae VII, X, XI. Also, compounds of Formula XXXIIcontaining a 17-oxo moiety can be converted to a corresponding compoundcontaining a 17fi-hydroxy- 17a-1OW6I alkenyl or lower alkynyl moiety bythe methods described above. Also, compounds of Formula XXXII can behydrolyzed to yield corresponding ll-hydroxy compounds of Formula XXXII,i.e. wherein E0 is hydroxy.

Condensation of the so-obtained compound of Formula XXXII or thecorresponding 17B-hydroxy, 17a-lower alkenyl or lower alkynyl compound(i.e. a compound of Formula VI containing a free or ll-esterifiedhydroxy group) then yields the desired end-product 96,10a-steroid orFormulae I-V containing an ll-hydroxy group. Such condensation can beeffected as described above for the preparation of a compound ofFormulae I-V from a compound of Formulae VI-XI. The so-obtained913,10ozsteroids containing an ll-esterified hydroxy group can behydrolyzed to the corresponding compounds containing an ll-hydroxygroup, which latter compounds are themselves useful as intermediates,for example, the ll-hydroxy group can be oxidized by methods known perse to yield corresponding ll-oxo steroids analogous to compounds ofFormulas I-V.

The pharmaceutically useful compounds prepared by the methods of thisinvention can be administered internally, for example, orally orparenterally, with dosage adjusted to individual requirements. They canbe administered in conventional pharmaceutical forms, e.g. capsules,tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of thisinvention. All temperatures are in degrees centigrade. The Florisiladsorbent used infra is a synthetic magnesia-silica gel available fromthe Floridin Company, PO. Box 989, Tallahassee, Fla. (cf. p. 1590, MerckIndex, 7th Ed. 1960). 200 mesh material was used. The moiety designatedby tetrahydropyranyloxy is tetrahydro- Z-pyranyloxy. When it is statedthat a procedure is effected in the cold, it should be understood thatit is commenced at 0 C. Throughout this application when compounds ofthe pregnane series are referred to it should be understood that it iscompounds of the Nil-pregnane series that are being referred to, unlessspecifically indicated to the contrary, and whether or not the compoundof the pregnane series is specifically indicated as of the Uri-series.

EXAMPLE 1 A solution of 3.2 g. of 17a-ethyltestosterone in 50 ml.methylene chloride and 25 ml. ethyl acetate was ozonized at 70(acetone-Dry Ice bath) until the solution was blue in color. Afteroxygen was passed through, the solution was evaporated at roomtemperature in vacuo. The syrupy residue was then dissolved in 100 ml.of glacial acetic acid, and after addition of 5 ml. of 30 percenthydrogen peroxide, left for 24 hours at 0-5. Following this time, it wasevaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2N sodium carbonate solution. The alkaline extract was poured in ice coldhydrochloric acid. The resultant crystalline 17a-ethyl-17,B-

hydroxy-5-oxo-3,5-seco A norandrostan-3-oic acid was filtered, washedwith water and dried. Upon being recrystallized from acetone, it meltedat 196197.

EXAMPLE 2 A solution of 1.5 g. of 17a-ethyl-17fl-hydroxy-5-oxo-3,S-seco-A-norandrostan-3-oic acid in 100 ml. of methanol was titratedwith 2 N sodium methoxide to the reddish color of phenolphthalein, andthen evaporated to dryness in vacuo, giving as the residue, the sodiumsalt of 17a-ethyl-17/3-hydroxy-5-oxo-3,5-seco-A-norandrostan- 3-oicacid. 5 g. of sodium-phenylacetate was added to the residue, and themixture pyrolyzed in vacuo 0.1 mm.) at 285295, for 2.5 hours. Thesublimate was dissolved in acetone, filtered and the filtrateconcentrated in vacuo. The resultant syrupy residue was chromatographedon a 60 g. Florisil (adsorbent) column. The fractions eluted withbenzene and 0.5 percent ethylacetate in benzene were combined and gave17m-ethyl-17/3-hydroxy-10a-desA-androstan-S-one, M.P. 94-95 afterrecrystallization from petroleum ether. The fractions eluted with 2percent and 5 percent ethylacetate in benzene were combined and gave17a-ethyl-17fi-hydroxy-105-desA androstan-S-one, M.P. 185185.5, aftertwo recrystallizations from pctroleum ether.

EXAMPLE 2a To a solution of 100 mg. of l7u-ethyl-l7 3-hydroxy-1OB-desA-androstan-S-one in 10 m1. of absolute ethanol was added oneequivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol.This reaction mixture was maintained at room temperature overnight, thenacidified with glacial acetic acid, poured in water and extracted withmethylene chloride. The extract was washed with water, dried overanhydrous sodium sulfate and concentrated in vacuo. Thin layerchromatography showed the product to be17a-ethyl-17,8-hydroxy-10a-desA-androstan- 5-one. It was obtainedcrystalline from petroleum etherether and melted at 89-95".

EXAMPLE 3 1.13 g. of 17a-ethyl-17fl-hydroxy-IOa-desA-androstan- 5-onewas dissolved in 120 ml. of anhydrous ether (or 1.13 g. of l 3-isomerwas dissolved in 300 ml. of anhydrous ether), and after cooling in asalt-ice bath, several drops of 30 percent hydrobromic acid in aceticacid were added. This was followed by the dropwise addition during fiveminutes of 0.684 g. of bromine dissolved in 2 ml. of acetic acid. Thisaddition was synchronized with the decoloration rate of the reactionmixture. Immediately after this, ml. of a saturated solution of sodiumbisulfite and 5 ml. of 2 N sodium carbonate solution were added. Themixture was then transferred into a separatory funnel, 500 ml. of etheradded, shaken and separated. The ether part was washed with water, driedand evaporated. The rsultant bromides were dissolved in 100 ml. ofdimethylformamide, and after addition of 3 g. of lithium carbonate, thesolution was heated at 100 for 45 minutes. After cooling, it was pouredinto one liter of ether, washed with water, 1 N hydrochloric acid, 2 Nsodium carbonate, water, dried and evaporated. The residue was dissolvedin 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. ofzinc powder added, and the so-formed mixture heated minutes at 80". Itwas then poured into one liter of ethylacetate and the resultantsolution washed with saturated sodium bicarbonate, then with water,dried and evaporated. The residue was chromatographed on Florisil(adsorbent) column. The fraction with benzene and /2 percentethylacetate in benzene gave regenerated starting material. Fractionswith 1 and 2 percent ethylacetate in benzene gave17ot-ethyl-17,8-hydroxy-desA androst-9-en-5-one, which after sublimation(140 and 0.1 mm. Hg vacuum), was obtained as a glass. [01],; -36.6(c.=1, CHCl 24 EXAMPLE 4 A suspension of 262 mg. of 5 percent rhodium onalumina catalyst in a mixture of 26 ml. of percent ethanol and 5.25 ml.of 2 N sodium hydroxide solution was pre-reduced, (i.e. hydrogenated atroom temperature and atmospheric pressure). To this was added a solutionof 262 mg. of 17a-ethyl-17fl-hydroxy-desA-androst-9-en-5-one in 15 ml.of 95 percent ethanol, and the mixture then hydrogenated at atmosphericpressure and room temperature. After one mole-equivalent of hydrogen wasabsorbed, the reaction was stopped, the catalyst was separated byfiltration, and the filtrate evaporated in vacuo. Glacial acetic acid (1ml.) was added to the residue, which was then dissolved in 1 liter ofether. The cloudy solution which resulted was washed with 2 N Na COsolution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined productschromatographed on a Florisil (adsorbent) column. The eluates with 1percent ethyl acetate in benzene gave first crystalline fractions, whichwere followed by non-crystalline fractions. The non-crystallinefractions were dissolved in ml. of methylene chloride, and after theaddition of 2.5 ml. of 2 percent CrO in 90 percent acetic acid, stirredovernight. The excess of chromic acid was removed by washing themethylene chloride solution with 10 ml. of 10 percent sodium hydrogensulfite solution, followed by washing with 2 N Na CO solution and thenwith water. It was then dried and evaporated in vacuo. The residue wasdissolved in 50 ml. of anhydrous ethanol containing 172 mg. of sodiumethoxide, and left overnight. The next day, after addition of 0.5 ml. ofglacial acetic acid, the solution was evaporated in vacuo, and theresidue was taken up in 1 liter of ether. The ether solution was washedwith 2 N Na CO solution, then with water, dried and evaporated. Theresidue was chromatographed on Florisil (adsorbent) column and gavecrystalline 17a-ethyl-175-hydroxy-desA-9 3,10fi-androstan-5-oneidentical (by thin layer chromatography) with the crystalline materialobtained in the first chromatographic separation. After tworecrystallizations from ether, it melted at 142-144"; [04 -11.65[methane], c.=1.245 percent].

EXAMPLE 5 To a solution of 132 mg. of 17a-ethyl-17/3-hydroxy-des-A-9l3,10B-androstan-5-one in 12.5 ml. of absolute ethanol containing 34mg. of sodium ethoxide, 0.15 ml. of freshly distilled methylvinyl ketonewas added. The reaction mixture was then refluxed for two hours in anitrogen atmosphere. After cooling the reaction mixture, 0.1 ml. ofglacial acetic acid was added thereto and the resulting mixture was thenpoured into 1 liter of ether. The resultant ether solution was washedwith water, dried over anhydrous sodium sulfate and evaporated in vacuo.The residue was chromatographed on fluorescent silicagel plates, withthe solvent system, 60 percent ethyl acetate-40 percent heptane. Thefiuoroescent part of the layers was extracted with ethyl acetate. Theresidue obtained after evaporation of ethyl acetate was firstcrystallized from ether-petroleum ether, then a second time from pureether, yielding 17a-ethyl-9p,wet-testosterone, M.P. 131-135".

EXAMPLE 6 glacial acetic acid, and after the addition of -5 ml. of 30percent hydrogen peroxide, left for 24 hours at 2 (in an ice box). Thesolution was then evaporated in vacuo, and the residue triturated withether yielding crystals. Re-

crystallization from acetone yielded l1a-hydroxy-3,5-seco-A-nor-pregnane-5,20 dione-3-oic acid 3,11-lactone, M.P. 253256. [M 193.3(c.=1, in chloroform).

EXAMPLE 7 A methanolic solution of 7.5 g. of 11a-hydroxy-3,5-seco-A-nor-pregnane-5,20-dione-3-oic acid 3,11 lactone was treated withone equivalent of 10 N sodium hydroxide solution and then evaporated todryness. Sodium phenylacetate (26 g.) was added to the so-obtainedsodium salt and the mixture pyrolyzed at 295 for two hours in vacuo. Thecrude sublimate was chromatographed on a silicagel column and elutedwith 10 percent ethylacetate in benzene. The amorphous solidllcc-hYdIOXY-lOoL-dGSA- pregnane-5,20-dine was first eluted from thecolumn. IR-spectrum in chloroform: 3620 and 3600 emf (-OH); 1706 cm?(carbonyl group). NMR-spectrum in deuterochloroform: a doublet for a-CHat 73.5 and 80.5 c.p.s. downfield from TMS at 60 mc./sec. Furtherelution of the column with 10 percent ethylacetate in benzene yieldedcrystalline l1a-hydroxy-IOfl-desA-pregnane- 5,20-dione which wasrecrystallized from methylene chloride-petroleum ether, M.P. 150152;+84.0 (c.=0.5 in absolute ethanol).

EXAMPLE 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml.of pyridine, there was added 100 mg. of11ahydroxy-1()B-desA-pregnane-5,20-dione. The mixture was then allowedto stand overnight at 2 (in a refrigerator), then was diluted with water(100 ml.) and extracted with chloroform (3X 150 ml.) and methylenechloride (100 ml.). The combined organic extracts were washed withwater, 1 N hydrochloride acid and again with water, then dried overanhydrous sodium sulfate and evaporated in vacuo. The crystallineresidue was recrystallized from ether, giving1lot-hydroxy-10B-desA-pregnane-5,20-dione methanesulfonate, M.P.139-140; [0:1 +46 (c.=0.5 in absolute ethanol).

EXAMPLE 9 A solution of 200 mg. of1la-hydroxy-lIB-desA-pregnane-5,20-dione methanesulfonate in 50 ml. ofdimethylformamide was refluxed for eight hours and then evaporated todryness. The residue was chromatographed on a Florisil (adsorbent)column. Elution with 2 percent ethylacetate/benzene and evaporation ofthe eluant yielded desA-pregn-9-ene-5,20-dione in the form of colorlessneedles, M.P. 111113. It was shown by mixed melting point to beidentical with a sample of the same compound prepared as described inExample 12.

EXAMPLE 10 chloroform) EXAMPLE 11 A solution of 12 g. of1la-rnesyloxy-progesterone in 300 ml. of methylene chloride/ethylacetate (2:1) was treated with azone at 70 until the solution becameblue in color. The excess of ozone was removed. by bubbling oxygenthrough the reaction mixture for five minutes. Methylene chloride wasthen removed under reduced pressure, and the solution diluted with ethylacetate to 200 ml. After addition of 12 ml. of 30 percent aqueoushydrogen peroxide, the reaction mixture was then allowed to standovernight at 2 (i.e., in the refrigerator), then evaporated to a volumeof ml. and diluted with ml. of benzene. The aqueous solution, obtainedby extraction with 8 portions of 75 ml. 2 N sodium carbonate followed bycombining the aqueous extracts was acidified with cold concentratedhydrochloric acid to pH 2 and extracted with methylene chloride. Thisextract was dried over anhydrous sodium sulfate and evaporated in vacuoto dryness. The residue crystallized when triturated with ether-acetonemixture, yielding crude 11a-mesoxy-5,20-dioxo-3i,5-seco-A-nor-pregnan-3-oic acid. After recrystallization fromacetone-petroleum ether, M.P. 152153; [M .+47.9 (c.=1, chloroform).

EXAMPLE 12 A solution of 6 g. of 11a-mesoxy-5,20-dioxo-3,5-seco-A-nor-pregnan-3-oic acid in ml. of methanol was mixed with a solution of1.5 g. of sodium carbonate in 55 ml. of water. The mixture was thentransferred into a 1 liter sublimination flask, and evaporated todryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetateis added, and after closing the top part of the apparatus, this mixturewas pyrolyzed at 290 and 0.02 mm. for four hours. The product, whichcollects on the cold finger, was dissolved in ether and filtered. Thefiltrate was then evaporated to dryness. Purification of the residue bychromatography on a 40 g. silica-gel column (benzene eluant) gavecrystalline desA-pregn-9-ene-5,20-d1one; M.P. Ill-113 (afterrecrystallization from ether). ,+56.8 (c.=0.25 percent in methanol).

EXAMPLE 13 To a solution of 1.2 g. of desA-pregn-9-ene-5,20-dione in 20ml. of methanol maintained at 0, there was slowly added a cooledsolution of 1.2 g. of sodium borohydride in 22 ml. methanol, and theresultant mixture was left for 72 hours at 0. It was then diluted with100 ml. of water and extracted with four 100 ml. portions of chloroform.The extract was dried over anhydrous sodium sulfate and evaporated invacuo, yielding a colorless oily product. This product was dissolved in250 ml. of chloroform and 6 g. of manganese dioxide was added to thesolution which was then stirred for 72 hours at room temperature,filtered and the filtrate evaporated to dryness in vacuo. The residuewas chromatographed on a silica-gel column and the eluates with 5percent ethyl acetate in benzene, after concentration gave crystalline20 3-hydroxydesA-pregn-9-en-5-one which upon recrystallization frommethylene chloride-petroleum ether formed colorless needles, M.P.122*123; [041 -=33 (c.=0.5, absolute ethanol).

EXAMPLE 14 A suspension of 262 mg. of 5 percent rhodium on aluminacatalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2N aqueous sodium hydroxide was hydrogenated at room temperature andatmospheric pressure. To this was added a solution of 262 mg. of20flhydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 percent ethanol, andthe reaction mixture then hydrogenated at room temperature andatmospheric pressure. After one mole equivalent of hydrogen wasabsorbed, the reaction was stopped, and the catalyst was separated byfiltration. After standing overnight the filtrate was concentrated invacuo. To the residue was added 1 ml. of glacial acetic acid, and it wasthen dissolved in 1 liter of ether. The cloudy solution was washed with2 N aqueous sodium carbonate solution, then with water, then dried overanhydrous sodium sulfate and evaporated to drynessv in vacuo. It yieldeda colorless oil, which Was chromatographed on a silica-gel column using1 percent ethyl acetate in benzene as the elutant. First eluted was20fl-hydroxy-IOa-desA-pregnan-S-one, M.P. 107-108 afterrecrystallization from methylene chloride/petroleum ether. R.D. (inmethanol); [M -25.3; [@1 -89; 274; [061 05 -1335; [0613 -116s.

Further elution yielded 20,8-hydroxy-9f3,IOB-desA-pregnan--one as acolorless oil. R.D. (in methanol); [@1 1400 1350 1310 EXAMPLE Asuspension of 262 mg. of 5 percent rhodium on alumina catalyst in amixture of 2 ml. of 3 N aqueous hydrochloric acid and 18 ml. 95 percentethanol was hydrogenated at room temperature and atmospheric pressure. Asolution of 262 mg. of ZOfl-hydroxy-desA-pregn- 9-en-5-one in 5 ml. ofabsolute ethanol was introduced into the hydrogenation flask, and thereaction mixture was then hydrogenated at room temperature andatmospheric pressure. After one mole-equivalent of hydrogen wasabsorbed, the reaction was stopped, the catalyst was separated byfiltration, and the filtrate neutralized with 2 N aqueous sodiumhydroxide solution. An excess of 5 ml. of 2 N aqueous sodium hydroxidewas added and the solution allowed to stand overnight. Ethanol was thenremoved by evaporation at reduced pressure, and after addition of 1 ml.of glacial acetic acid, it was extracted with 1 liter of ether. Theextract was washed with 2 N aqueous sodium carbonate solution, then withwater, dried and concentrated in vacuo. It gave a colorles oil, whichwas chromatographed on a silica-gel column using 2 percent ethyl acetatein benzene as the elutant. The first fractions of the eluate yielded,upon concentration, fl-hydroxy-10a-desA-pregnan-5-one. From theimmediately subsequent fraction, 20fl-hydroxy-9/3,IOB-desA-pregnan-S-one was obtained. Both products were identical with the same compoundsobtained in Example 14.

EXAMPLE 16 20B hydroxy 95,1011 pregn-4-en-3-one is prepared bycondensation of 20,8-hydroxy-9fi,IOB-desA-pregnan-S- one with methylvinyl ketone according to the procedure of Example 5. The product meltat 176.5-178.5; [(11 -l43 (chloroform).

EXAMPLE 17 A medium is prepared of 20 g. of Edamine enzymatic digest ofl l min, 3 g. of corn steep liquor and 50 g. of technical dextrosediluted to 1 liter with tap water and adjusted to a pH of 4.3-4.5.Twelve liters of this sterilized medium is inoculated with Rhizopusnigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at 28using a rate of aeration and stirring such that the oxygen uptake is6.3-7 millimoles per hour per liter of Na SO according to the method ofCooper et al., Ind. Eng. Chem, 36, 504 (1944). To this medium containinga 24 hour growth of Rlzizopus nigricans minus strain, 6 g. of17ot-acetoxyprogesterone in 150 ml. of acetone is added. The resultantsuspension of the steroid in the culture is incubated under the sameconditions of temperature and aeration for an additional 24 hour periodafter which the beer and mycelium are extracted. The mycelium is thenfiltered, washed twice, each time with a volume of acetone approximatelyequal in volume to the mycelium, extracted twice, each time with avolume of methylene chloride approximately equal to the volume of themycelium. The acetone and methylene chloride extracts including solventare then added to the beer filtrate. The mixed extracts and beerfiltrate are then extracted successively with 2 portions of methylenechloride, each portion being /2 the volume of the mixed extracts andbeer filtrate, and then with 2 portions of methylene chloride, eachportion being A the volume of the mixed extracts and beer filtrate. Thecombined methylene chloride extracts are then washed with 2 portions ofa 2 percent aqueous solution of sodium b1- carbonate, each portion being,1 the volume of the cornbined methylene chloride extracts. Themethylene chloride extracts are then dried with about 3-5 g. ofanhydrous sodium sulfate per liter of solvent, and then filtered. Thesolvent is then removed from the filtrate by distillation,

17a acetoxy 5,20 dioxo-l1a-mesoxy-A-nor-3,5-secopregnan-3-oic acid isprepared by ozonolysis of 17a-acetoxy-l la-mesoxy-progesterone,according to the procedure of Example 11.

EXAMPLE 19 17a acetoxy-desA-pregn-9-ene-5,20-dione is prepared from17a-acetoxy-5,20-dioxo-11a-mesoxy-A-nor-3,5-secopregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 12.

EXAMPLE 20 17a acetoxy 20;; hydroxy-desA-pregn-9-en-5-one is preparedfrom l7a-acetoxy-desA-pregn-9-en-5,20-dione by reduction and reoxidationaccording to the procedure of Example 13.

EXAMPLE 21 17a acetoxy 20,8 hydroxy-9fi,IOB-desA-pregnan-S- one isprepared from acetoxy-20fl-hydroxy-desA- pregn-9-en-5-one byhydrogenation under acidic conditions in the presence of a rhodiumcatalyst according to the procedure of Example 15.

EXAMPLE 22 17a acetoxy 20;? hydroxy-95,10a-pregn-4-en-3-one is preparedby condensing methyl vinyl ketone with 170:- acetoxy 20/3 hydroxy9[3,10fi desA-pregnan-S-one according to the procedure of Example 5except instead of conducting the condensation in absolute ethanol andcatalyzing it with sodium ethoxide, the condensation is conducted inacetic acid and is catalyzed with p-toluene sulfonic acid.

EXAMPLE 23 20B hydroxy 4 methyl-95,10a-pregn-4-en-3-one is prepared bycondensing 20fi-hydroxy-9B,IOB-desA-pregnan-S-one and ethyl vinyl ketoneaccording to the procedure of Example 5.

EXAMPLE 24 hydroxy 5 oxo-3,5-seco-A-nor-androstan-3-oic acid is preparedby ozonolysis of testosterone according to the procedure of Example 1.

EXAMPLE 25 17B hydroxy 10a desA-androstan-S-one and 1718- hydroxy 10BdesA androstan-S-one are prepared from 176 hydroxy 5oxo-3,5-seco-A-norandrostan-3-oic acid by conversion of the latter toits sodium salt followed by pyrolysis, according to the procedure ofExample 2.

EXAMPLE 26 17 3 hydroxy desA androst-9-en-5-one is prepared from 17,8hydroxy 10a-desA-androstan-5-one by bromination followed bydehydrobromination, according to the procedure of Example 3.

EXAMPLE 26a DesA-androst-9-ene-5,17-dione is prepared from 176-hydroxy-desA-androst-9-en-5-one by oxidation of the latter with a 2percent chromic acid solution in 90 percent acetic acid. The so-0btaineddesA-androst-9-ene-5,17-

dione is recrystallized from cyclohexane and melts at 123-1235;

139 +83 (c.=0.1021, dioxane).

Example 27 A solution of 236 mg. of 17ii-hydroxy-desA-androst-9-en-S-one in 40 ml. 95 percent ethanol and 5.25 ml. 2 N aqueous sodiumhydroxide solution was hydrogenated with one mole equivalent of hydrogenover 236 mg. of prereduced 5 percent rhodium on alumina catalyst. Afterseparation of catalyst, the solution was concentrated in vacuo todryness, and the residue taken up in one liter of ether. The ethersolution was washed with Water, dried over anhydrous sodium sulfate andevaporated to dryness in vacuo. From the residue17fl-hydroxy-9'B,IOB-desA- androstan-S-one was obtained bycrystallization. M.P. 144.5-145"; [011 -22 (c. =0.103; dioxane). The175- acetate (i.e. 17B-acetoxy-9fi,IOB-desA-androstan-S-one) is obtainedby acetylation of testosterone followed by ozonolysis, pyrolysis,bromination and dehydrobromination, and reduction according to themethods of Examples 24, 25, 26 and 27 respectively, and melts at 118-119; 28 (c.'=0.103; dioxane).

EXAMPLE 28 A solution of 238 mg. of 17B-hydroxy-9fi,10/3-desA-androstan-S-one, 1 ml. of ethylene glycol and catalytic amount ofp-toluene sulfonic acid in 100 ml. of anhydrous benzene was slowlydistilled until no more water was coming over. The solution was thenconcentrated in vacuo to a small volume, and 17,6-hydroxy-9p3,10,6-desA-andrOstan-S-one S-ethylene ketal was obtained from the residue bycrystallization. M.P. 115-116"; -9 (c. =0.0987; dioxane).

EXAMPLE 29 To a solution of 282 mg. of l7fi-hydroxy-9BJGB-desA-androstan-S-one 5-ethylene ketal in 50 ml. of methylene chloride wasadded 1 equivalent of 2 percent chromic acid in pyridine, and thereaction mixture then stirred overnight. The reaction mixture was thenwashed with 10 percent aqueous sodium hydrogen sulfite, 2 N aqueoussodium carbonate, water, then dried over anhydrous sodium sulfate andconcentrated in vacuo to dryness. Crystallization of the residue gave9,8,10B-desA-androstanc-5,17-dione 5-mono-ethylene ketal. Splitting ofthe ketal in acetone solution in the presence of a catalytic amount ofp-toluene sulfonic acid gives 9,B,ll3-desA- androstane-5,17-dione whichmelts, after recrystallization from cyclohexane, at 775-78"; [111 +55(c.=O.107; dioxane).

EXAMPLE 30 To a preformed solution of one mole equivalent ofprop-l'-inyl lithium in 100 ml. of anhydrous liquid ammonia was addedtetrahydrofuran solution of 200 mg. of9,8,lOfl-desA-androstane-S,17-dione mono-ethylene ketal,, and thereaction mixture stirred for two hours. After addition of one gram ofammonium chloride, cooling was discontinued, and the reaction mixtureallowed to evaporate. The residue was extracted with methylene chloride,the extract was washed with water, dried over anhydrous sodium sulfateand evaporated. The residue was dissolved in 20 ml. of acetone and thecatalytic amount of p-toluenesulfonic acid added, and the solution wasrefluxed for two hours, then poured in water and extracted in methylenechloride. The methylene chloride extract was Washed with water, thendried over anhydrous sodium sulfate and evaporated to dryness in vacuo.Crystallization of the residue gave 17a-(prop-l'-inyl)-17fl-hydroxy-9fi,10fl-desA-androstan-S-one.

EXAMPLE 31 17w(prop-1'-inyl)-17,3-hydroxy 9,8,100: androstan- 4-en-3-oneis prepared by condensing methyl vinyl ketone 30 with 17a-(prop-1'-inyl)17B hydroxy-9B,10B-desA- androstan-S-one according to the procedure ofExample 5. The product melts at 164165.

EXAMPLE 32 To a stirred solution of one mole equivalent of 2-methyl-prop-Z-enyl magnesium bromide in 100 ml. of other at roomtemperature was added dropwise a solution of 280 mg. of',lOfl-desA-androstane-S,l7-dione 5-monoethylene ketal in ml. oftetrahydrofuran. The reaction mixture was refluxed for one hour. Aftercooling in an ice-salt bath, a saturated solution of sodium sulfate wasslowly added to decompose the Grignard complex. This was followed byaddition of anhydrous sodium sulfate. The solution was separated byfiltration and concentrated in vacuo to dryness. The solution of theresidue and of a catalytic amount of p'toluene sulfonic acid in 20 ml.of acetone was refluxed for two hours, then poured in water andextracted in methylene chloride. Methylene chloride extract was washedwith water, dried over anhydrous sodium sulfate and evaporated todryness. From the residue t-(2-methyl-prop-2'-enyl) 17,8 hydroxy-9B,l0{3desA-androstan-S-one was obtained.

EXAMPLE 3s 17ot-(2'-methyl-prop 2enyl)-17B-hydroxy-9fl,10aandrost-4-en-3-one is prepared froml7u-(2-methyl-prop- 2'-enyl)-l7fl-hydroxy-9li,IOB-desA-androstan 5 oneby condensation of the latter with methyl vinyl ketone according to theprocedure of Example 5. The product melts at 106-108.

EXAMPLE 34 16u-acetoxy-20ethylenedioxy-pregn 4 en-3-one is prepared byacylation of 16ot-hydroxy-20-ethylenedioxypregn-4-ene-3,20-dione withone equivalent of acetic anhydric in pyridine solution at roomtemperature for 2 hours, followed by concentration to dryness in vacuo.16u-acetoxy-20-ethylenedioxy 5 oxo-3,5-seco-A-norpregnan-3-oic acid isprepared by ozonolysis of 16aacetoxy-20-ethylenedioxy-pregn-4-en-3-oneaccording to the procedure of Example 1.

EXAMPLE 35 16u-acetoxy-20-ethylenedioxy 10a desA-pregn-S-one and 16aacetoxy-ZO-ethylenedioxy-IOB-desA-pregnan-S- one are prepared from16a-acetoxy-20-ethylenedioxy-S- oxo-3,5-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis(according to the procedure of Example 2) and reactylation with aceticanhydride and pyridine.

EXAMPLE 36 16a-acetoxy 20 ethylenedioxy-desA-pregn-9 en-5- one isprepared from 16u-acetoxy-20-ethylenedioxy-lOadesA-pregnan-S-one bybromination followed by dehydrobromination, according to the procedureof Example 3.

EXAMPLE 37 l6a-acetoxy 20 ethylenedioxy-9fi,IOB-desA-pregnan- 5-one isprepared from 16ot-acetoxy-ZO-ethylenedioxydesA-pregn-9-en-5-one byhydrogenation under basic conditions in the presence of a rhodiumcatalyst, according to the procedure of Example 14.

EXAMPLE 38 16u-hydr0xy 20 ethylenedioxy-9B,10ot-pregn-4-en-3- one isprepared by condensingl6a-acetoxy-20-ethylenedioxy-desA-9B,IOfiregnan-S-one with methyl vinylketone according to the procedure of Example 5.

EXAMPLE 39 3fl-hydroxy-1'6a-methyl-pregn 5 en-20-one ethylene ketal isprepared by ketalization of 3,8-hydroxy-16otmethyl-pregn-S-en-ZO-one inbenzene solution with ethylene glycol using p-toluenesulfonic acid ascatalyst. Pyridine-chromic acid oxidation of the so-obtained3,8-hydroxy-16u-methyl-pregn-S-en-ZO-one ethylene ketal yields16a-methyl 20 ethylenedioxy-pregn-4-en-3-one.16amethyl-20-ethylenedioxy-5-oxo-3,5-seco A norpregnane-3-oic acid isprepared by ozonolysis of 16a-methyl- 20-ethylene-dioxy-pregn-4-en-3-oneaccording to the procedure of Example 1.

EXAMPLE 40 16or-methyl 20 ethylenedioxy-lOa-desA-pregnan-S- one and16a-methyl-20-ethylenedioxy-lOfl-desA-pregnan- S-one are prepared from16a-methyl-20-ethylenedioxy-5- oxo-3,S-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 41 16a-methyl 20 ethylenedioxy-desA-pregn-9-en-5-one is preparedfrom 16a-methyl-ZO-ethylenedioxy-IOa-desA- pregnan-S-One by brominationfollowed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 42 16oz methyl-20-ethylenedioxy-9(3,IOfi-desA-pregnan-S- one isprepared from 16a-methyl-20-ethylenedioxy-desA- pregn-9-en-5-one byhydrogenation under basic conditions in the presence of a rhodiumcatalyst, according to the procedure of Example 14.

EXAMPLE 43 16a rnethyl-20-ethylenedioxy-9fi,l0a-pregn-4-en-3-one isprepared by condensing 16a-methyl-20-ethylenedioxy-9/3,IOfi-desA-pregnan-S-one with methyl vinyl ketone, according to theprocedure of Example 5.

EXAMPLE 44 21-acetoxy llu hydroxy 20 ethylenedioxy-pregn-4- en-3-one isprepared by microbiological treatment of21-acetoxy-20-ethylenedioxy-pregn-4-en-3-one, according to the procedureof Example 17. 21-acetoxy-1la-mesoxy- 20-ethylenedioxy-pregn-4-en-3-oneis prepared by treatment of21-acetoxy-11a-hydroxy-20-ethylenedioxy-pregn- 4-ene-3-one withmethanesulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 45 21-acetoxy-1-1u-mesoxy 20 ethylenedioxy--oxo-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 2l-acetoxy-11a-mesoxy-20-ethylenedioxy-pregn-4-e11-3- one, according to theprocedure of Example 11.

EXAMPLE 46 21-acetoxy-20-ethylenedioxy desA pregn-9-en-5-one is preparedfrom 2l-acetoxy-ZO-ethylenedioxy-lla-mesoxy 3,5-seco-A-norpregnan-3-oicacid by conversion of the latter to its sodium salt followed bypyrolysis, according to the procedure of Example 12, except that thecrude product is reacetylated by treatment with aceticanhydride/pyridine prior to its being worked-up.

EXAMPLE 47 21-acetoxy-20-ethylene 95,105 desA pregnan-S-one is preparedfrom 21-acetoxy-20-ethylenedioxy-desA-pregn- 9-en-5-one by hydrogenationunder acidic conditions in the presence of a rhodium catalyst, accordingto the procedure of Example 15.

EXAMPLE 48 21-hydroxy-20-ethylenedioxy 9 3,100: pregn-4-ene-3- one isprepared from 21-acetoxy-20-ethylenedioxy-918,106- desA-pregnan-S-one bycondensing the latter with methyl vinyl ketone, according to theprocedure of Example 22. EXAMPLE 4'9 11ozmesoxy-16a,17a-isopr0pylidenedioxy-progesterone is prepared by treatmentof 1la-hydroxy-lfia,Hot-isopropylidenedioxy-progesterone with methanesulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 50 5,20-dioxo-11a-mesoxy :,1711 isopropylidenedioxy-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of11a-mesoxy-16a,17a-isopropylidenedioxy-progesterone, according to theprocedure of Example 11.

EXAMPLE 51 16a,Hot-isopropylidenedioxy desA pregn-9-en-5,20- dione isprepared from5,20-dioxo-11a-mesoxy-16u,17aisopropylidenedioxy-3,5-seco-A-norpregnan-3-oicacid by conversion of the latter to its sodium salt, followed bypyrolysis according to the procedure of Example 12.

EXAMPLE 52 20,8 hydroxy 160:,171: isoipropylidenedioxy desA-pregn-9-en-5-one is prepared from16u,l7o-isopropylidenedioxy-desA-pregn-9-ene-5,20-dione by reduction andreoxidation, according to the procedure of Example 13.

EXAMPLE 5 3 20/3 hydroxy 16a,17a isopropyidenedioxy 9153,1013-desA-pregnan-S-one is prepared from 20fl-hydroxy-16a,17a-isopropylidenedioxy-desA-pregn-9-en-S-one is hydrogenation accordingto the procedure of Example 14.

EXAMPLE 54 20/3-hydroxy 16a,l7a isopropylidenedioxy 918,100:-pregn-4-en-3-one is prepared by condensing methyl vinyl ketone with20/3-hydroxy l6a,17a isopropylidenedioxydesA-9fl,10,B-pregnan-5-oneaccording to the procedure of Example 5.

EXAMPLE 55 7a,17a-dimethy1 1718h'ydroxy-5-oxo-3,S-seco-A-norandrostan-B-oic acid is prepared from7a,17a-dimethyltestosterone by ozonolysis of the latter, according tothe procedure of Example 1.

EXAMPLE 5 6 7a,17a-dimethyl-17B-hydroxy 10oz desA-androstan-5- one and7a,l7a-dimethyl l7fi-hydroxy-IOB-desA-androstan-S-one are prepared from7a,17a-dimethyl-17fl-hydroxy-5-oxo-3,S-seco-A-norandrostan-3-oic acid byc0nversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 57 7a,17a-dimeth'yl 17B hydroxy-desA-androst-9-en-5- one isprepared from 7a,17a-dimethyl-17/9-hydroxy-10a- EXAMPLE 61 lla-mesoxy17a methyl 5,20 dioxo-3,5-sec-A-norpregnan-3-oic acid is prepared from11a-mesoxy-17amethyl-progesterone by ozonolysis of the latter, accordingto the procedure of Example 11.

EXAMPLE 62 170: methyl-desA-pregn-9-ene-5,20-dione is prepared from 110:mesoxy-17u-methyl-5,20-dioxo-3,S-seco-A-norpregnan-3-oic acid byconversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 12.

EXAMPLE 63 20fl-hydroxy-17a-methyl-desA-pregn-9-en-S-one is preparedfrom 170: methyl-dcsA-pregn-9 en-5,20-dione according to the procedureof Example 13.

EXAMPLE 64 20/3-hydroxy-17a-methyl-9B,IOB-desA-pregnan-S-one is preparedfrom 17a-methyl-2OB-hydroxy-desA-pregnan-9- ene-S-one according to theprocedure of Example 15.

EXAMPLE 65 EXAMPLE 66 A solution of 12.8 g. of 17a-methyltestosterone in200 ml. of methylene chloride and 100 ml. of ethyl acetate was ozonizedfor 1 hour and 5 minutes at -70 (acetone-Dry Ice bath) until a bluecolor developed. After oxygen was bubbled through, the solution was thenconcentrated at room temperature in vacuo. The residue was dissolved in400 ml. of acetic acid, and after addition of 30 ml. of 30% hydrogenperoxide, the solution was left overnight at It was then evaporated todryness in vacuo, the residue taken up in ether, and the ether solutionextracted with 2 N aqueous sodium carbonate (12X 50 ml.). The combinedcarbonate extracts were cooled in ice, and acidified with concentratedhydrochloric acid. The aqueous suspension of precipitated organic acidwas extracted with methylene chloride, this extract was washed withwater, dried over anhydrous sodium sulfate and evaporated giving as acolorless crystalline material 1713- hydroxy 17amethyl--oxo-3,S-seco-A-nor-androstan-3- oic acid. Afterrecrystallization from acetone-hexane, it melted at 195-197", [a] =9.8(c.=l.0 in chloroform).

EXAMPLE 67 A solution of g. of 17f3-hydroxy-17a-methyl-5-oxo-3,5-seco-A-nor-androstan-3-oic acid in 250 ml. of methanol was madealkaline to phenolphthalein with sodium ethoxide, and evaporated todryness. The residual powdery sodium salt was mixed well with 32 g. ofsodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), andthe mixture heated at 290 in vacuo for 4 hours. After cooling to roomtemperature, a large excess of water was added, and the resultantsuspension extracted with 2 liters of ether. The ether extract waswashed with water, aqueous 2 N sodium carbonate solution, and again withwater, dried and evaporated. This gave a sirupy residue, which by thinlayer chromatograms and infrared spectra consisted of 175hydroxy-17u-methyl-10a-desA- androstan-S-one as the major and17fl-hydroxy-17u-methyl-10fl-desA-androstan-5-one as the minor product.

Three additional pyrolyses were performed as described above, and thecombined products so-obtained was chromatographed on a 850 g. silica gelcolumn, using 5% ethylacetate in benzene as the eluent. Thischromatography yielded 17/3 hydroxy-17a-methyl-IOa-desA-androstan-S-one, which after recrystallization from petroleum ether melted at 9697,[a] =28.2 (C.=0.5 in chloroform).

Further eluates of the column gave product,17/3-hydroxy-17a-methyl-1OB-desA-androstan-S-one which, whenrecrystallized from ether, melted at 165-167,

(c.=0.5 in chloroform).

To a solution of 2.2 g. of the mixture of 17,8-hydroxy-17a-methyl-10a-desAandrostan-5-one and 17,3-hydroxy- 17amethyl-IO/S-desA-androstan-S-one (obtained by the above pyrolysisprocedure) in 50 ml. of absolute ethanol were added 20.1 ml. of asolution prepared by dissolving 2.48 g. of sodium metal in 250 m1. ofabsolute ethanol. The reaction mixture was stirred overnight at roomtemperature. It was then acidified with 2 ml. of glacial acetic acid,and evaporated to dryness. The residue was extracted in ether 1 liter)and the ether extract washed with water,

dried, and evaporated. The residue was crystallized from petroleum ethergiving a quantitative yield of1713-hydroxy-l7a-methyl-10a-desA-androstan-5-one.

EXAMPLE 68 To a solution of 11.2 g. of 17,3-hydroxy-17a-methyl10a-desA-androstan-5-one in 1260 ml. of anhydrous ether, stirred andcooled in an ice-salt, were added first several drops of 30% hydrogenbromide in acetic acid, then dropwise a solution of 7.16 g. of brominein 20 ml. of glacial acetic acid. The rate of addition of the brominesolution was synchronized with the rate of disappearance of excessbromine. After brominatiou was complete, 53 ml. of 10% sodium hydrogensulfite solution and 53 ml. of aqueous 2 N sodium carbonate solutionwere added to the reaction mixture while stirring. The ether layer wasthen separated, washed with water, dried, and evaporated to dryness invacuo. The residue was dissolved in 250 ml. of dimethylformamide, andheated with 7.5 g. of lithium carbonate at 100 for 45 minutes. Aftercooling, 2 liters of ether were added and the ether solution washed withwater, 1 N hydrochloric acid, and then again with water, dried andevaporated. The residue was dissolved in 200 ml. of glacial acetic acid,12.6 g. of sodium acetate and 12.6 g. of zinc powder were added and themixture heated for ten minutes at After cooling to room temperature, thereaction mixture was filtered, and evaporated. The residue was dissolvedin ethylacetate, and washed with saturated sodium bicarbonate solution,then with water, dried and evaporated. The so-obtained residue waschromatographed on a silica gel column using 10% ethylacetate in benzeneas the eluent which gave first 17/3-hydroxy- 17amethyl-10ct-(ltiSA-iilldI'OStfiIl-S-OHG, followed by 17/3- hydroxy 17amethyl-desA-androst-9-en-5one. After recrystallization from ether, thelatter compound melted at 103104, [a] =-63.2 (c.=0.5 in chloroform).

EXAMPLE 69 A suspension of 1.25 g. of 5% rhodium on alumina catalyst ina mixture of 130 ml. of 95% ethanol and 26 ml. of 2 N sodium hydroxidewas prereduced. To this was then added a solution of 1.25 g. of17B-hydroxy-17amethyl-desA-audrost-9-en-5-one in 75 ml. of 95 ethanol,and then mixture was hydrogenated at atmospheric pressure and roomtemperature. After one mole equivalent of hydrogen was absorbed, thereaction was stopped, the catalyst was removed by filtration, and thefiltrate evaporated in vacuo. To the residue 5 ml. of glacial aceticacid was added, the so-formed mixture then dissolved in 2 liters ofether, and the resultant cloudy solutionwas washed with water, thendried and evaporated. The residue was dissolved in 50 ml. of methylenechloride and oxidized with 5 ml. of 2% chromic acid in acetic acid untilgreen color of reaction mixture. After then being washed with sodiumhydrogen sulfite solution 2 N sodium carbonate solution and water, thereaction mixture was dried over sodium sulfate and evaporated. Theresidue was chromatographed very slowly on a 50 g. silica gel column,with 5% ethylacetate in benzene, and followed with thin layerchromatography. First, 17p hydroxy-17a-methyl-9a,10a-

desA-androstan-S-one was eluted. After a minoramount of mixed material,17fl-hydroxy-l7u-methyl-9f3,IOB-desA- androstan-S-one was eluted. Afterrecrystallization from ether-petroleum ether, it melted at 94-96.

EXAMPLE 70 17a-methyl-9 9,10at-testosterone is prepared from17amethyl-l7B-hydroxy-desA-9B,IOB-androstan-S-one by condensation of thelatter with methyl vinyl ketone, according to the procedure of Example5. The product melts at 128-129".

EXAMPLE 71 A solution of 6 g. of 11u,20fi-diacetoxy-pregn-4-en-3- one in100 ml. methylene chloride and 50 ml. of ethylacetate was ozonized at--70. After methylene chloride was removed by distillation in vacuo, theresidual solution was diluted to 100 ml. with ethylacetate. To this ml.of 30 percent hydrogen peroxide was added and left overnight at roomtemperature. The reaction mixture was concentrated to dryness in vacuo,the residue taken up in 1 liter of ether, and the resulting solutionextracted times with 50 ml. portions of 2 N aqueous sodium carbonate.The carbonate extract was then acidified with ice-cold concentratedhydrochloric acid. The precipitated product was separated by filtration,and crystallized to give l1u,20;3diacetoxy-S-oxo-3,5-seco-A-nor-pregnan-3- oic acid.

EXAMPLE 72 Bromination and dehydrobromination starting with1la,20,B-diacetoxy-IOB-desA-pregnan-S-one according to the procedure ofExample 3, gave 1la,20,8-diacetoxydesA-pregn-9-en-5-one.

EXAMPLE 74 Hydrogenation of 1la,20/8-diacetoxy-desA-pregn-9-en- 5-one inethanolic hydrochloric acid over 5 percent rhodium on alumina catalystat room temperature and atmospheric pressure according to the procedureof Example gave 1la,20 8-diacetoxy-9}3,IO/B-desA-pregnan-S- one.

EXAMPLE 75 1la,20/3-diacetoxy-9[3,IOB-desA-pregnan-S-one was hydrolyzedin methanol solution with one mole equivalent of potassium carbonate togive 11a,20/3-dihydroxy-9{3,10/8- desA-pregnan-S-one.

EXAMPLE 76 Condensation of 11a,20fi-dihydroxy-98,IOfl-desA-pregnan-5-one with methyl vinyl ketone according to theprocedure of Example 5 gave 11a,20fl-dihydroxy-9p,10apregn-4-en-3-one.

EXAMPLE 77 A solution of 3 g. of 17a-ethyl-17 3-hydroxy-androsta-1,4-dien-3-one in 75 ml. of methylene chloride and 25 ml. of ethylacetate was ozonized at 70 till it became blue. After evaporation todryness, the residue was dissolved in 100 ml. of glacial acetic acidcontaining 5 ml. of 30 percent hydrogen peroxide, and set at roomtemperature for 2 days. The reaction mixture was concentrated to drynessand the residue dissolved in one liter of ether. The ether solution wasthen extracted 10 times with 25 ml. portions of aqueous 2 N sodiumcarbonate solution, and the carbonate extracts were acidified withice-cold concentrated hydrochloric acid. The non-crystalline precipitatecontaining 17a-ethyl-17/9-hydroxy-10acarboxy-desA-androstan-5-one wasseparated by filtration and dried, then dissolved in 135 ml. of absoluteethanol, and after addition of 9 ml. of aqueous 2 N sodium hydroxide,boiled for 1 hr. The reaction mixture was concentrated in vacuo to asmall volume, and diluted with 1750 m1. of ether. The ether solution waswashed with water, dried over anhydrous sodium sulfate, and concentratedin vacuo to dryness. The residue was crystallized from ether-petroleumether, to give l7a-ethyl-17B-hydroxy-10a-desA-androstan-5-one, M.P.89-90".

EXAMPLE 78 3-(1718 hydroxy-S-oxo-3,S-seco-A-nor-androstan-17ayl-3-oicacid)-propionic acid lactone is prepared by ozonolysis of3-(3-oxo-17,3-hydroxy-androst-4-en-17a-yl)-pro pionic acid lactone,according to the procedure of Example 1.

EXAMPLE 79 3 (17,3 hydroxy-S-oxo-10ot-desA-androstan-17a-yl)- propionicacid lactone and 3-(l7fl-hydroxy-5-oxo-1OB-desA-androstan-l7a-yl)-propionic acid lactone are prepared from3-(17fl-hydroxy-5-oxo-3,5-seco-A-nor-androstan-17a-yl-3-oicacid)-propionic acid lactone by conversion of the latter to its sodiumsalt followed by pyrolysis, according to the procedure of Example 2.

EXAMPLE 8O 3-(17 8 hydroxy-5-oxo-desA-androst-9-en-l7a-yl)-propionicacid lactone is prepared from 3-(17fi-hydroxy-5- oxol Oa-desA-andrOstanl7a-yl -propionic acid lactone by brornination followed bydehydrobromination, accord ing to the procedure of Example 3.

EXAMPLE 81 3 (17,3 hydroxy-5-oxo-9/3,IOB-desA-androstan-Uayl)-propionicacid lactone is prepared from 3( 17,8-hydroxy 5oxo-desA-androst-9-en-l7a-yl)-propionic acid lactone by hydrogenation inthe presence of a rhodium catalyst, according to the procedure ofExample 4.

EXAMPLE 82 3 (17,3 hydroxy-3-oxo-9fl,10u-androst-4-en-17a-yl)- propionicacid lactone is prepared by condensing 3-(17fihydroxy 5 oxo-93,lOfl-desA-androstan-l7a-yl)-propionic acid lactone with methyl vinylketone, according to the procedure of Example 5.

EXAMPLE 83 17oz,20;20,21 bis-methylenedioxy-llot-mesyloxy-pregn-4-en-3-one is prepared by treatment of 17a,20;20,2l-bi8methylenedioxy-l1u-hydroxy-pregn-4-en-3-one with methanesulfonylchloride according to the procedure of Ex ample 10.

EXAMPLE 84 17a,20;20,21 bis-methylenedioxy-lla-mesyloxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis ofl7a,20;20,2l-bis-methylenedioxy-lla-mesyloxypregn-4-en-3-one accordingto the procedure of Example 11.

EXAMPLE 85 17a,20;20,21 bis methylenedioxy-desA-pregn-9-en-5- one isprepared from l7a,20;20,2l-bis-rnethylenedioxy-1la-mesyloxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid by conversion of thelatter to its sodium salt followed by pyrolysis, according to theprocedure of Example 12.

EXAMPLE 86 17a,20;20,21 bis methylenedioxy-9fi,IOB-desA-pregnan-S-one isprepared from 17a,20;20,2l-bis-methylenedioxy-desA-pregn-9-en-5-one byhydrogenation in the presence of a rhodium catalyst according to theprocedure of Example 14.

37 EXAMPLE s7 17a,20;20,21 bis methylenedioxy-9fl,l0cz-pregn-4-en- 3-oneis prepared by condensing methylvinyl ketone with17a,20;20,21-bis-methylenedioxy-9;3,10,8-desA-pregnan-S-one, accordingto the procedure of Example 5.

EXAMPLE 88 ZOfl-hydroxy 95,100 pregna-1,4-dien-3-one was prepared bycondensation of 20fi-hydroxy-9fl,IOQ-desA-pregnan-S-one with 1equivalent of methyl ethinyl ketone in boiling benzene solution,catalyzed by sodium hydride.

EXAMPLE 89 One ml. of Jones reagent (0.004 mole CrO is added to 200 mg.of 175-hydroxy-9B,10p-desA-androstan-5-one in 20 n11. of acetone at 10.The mixture is then left for minutes at room temperature, and 5 ml. ofethanol then added. The resulting suspension is evaporated to dryness invacuo, water is added to the residue and the undissolved moiety taken upin ether. The ether phase is then washed with a solution of sodiumbicarbonate and then with water, dried over sodium sulfate andevaporated to dryness. There is so obtained an oil which crystallizesupon the addition of a small portion of petroleum ether. The so-obtainedcrystals of 95,105-desA-androstane-S,17- dione melt, afterrecrystallization from cyclohexane, at 77.578;

(c.=0.108, dioxane); R.D. in dioxane (c.=0.107%): A in m ([a]-value in550 (+70); 400 (+297); 350 (+798); 320 (+2968) max.; 300 (+467); 299(0); 290 (1890).

EXAMPLE 90 A solution of 250 mg. of 17fi-hydroxy-9B,10B-desA-androstan-S-one dissolved in 2.5 ml. of pyridine and 2.5 m1. of aceticanhydride, is left at room temperature for 18 hours. The mixture is thenevaporated to dryness at 80/ 11 mm., the residue taken up in ether, andthe ether phase washed with 1 N hydrochloric acid, sodium bi- EXAMPLE 91A solution of 250 mg. of 17,3-acetoxy-9B,IOB-desA- androstan-S-one in 60ml. of 95% methanol containing 144 mg. of potassium hydroxide isrefluxed for 60 mmutes. The resulting mixture is evaporated to drynessin vacuo, water added to the residue and the suspension extracted withether. The ether phase is washed with water, dried over sodium sulfate,filtered off, the solvent removed and the crystalline residue thencrystallized from a small volume of cyclohexane, yielding crystals of17,8- hydroxy-9,8,IOB-desA-androstan-S-one which upon beingrecrystallized from ethylacetate melt at 144.5-145";

]9=22 (c.-=0.103, dioxane), R.D. in dioxane (c.=0.103); x in mp.([a]-value in 400 (7); 390 (0); 350 (+52); 313 (+571) max.; 307 (+492)min.; 305 (+504) max.; 300 (+324); 293 (0); 290 (202).

EXAMPLE 92 A solution of 10 g. of 1lfi-formyloxy-androsta-l,4-diene-3,17-dione in 100 ml. of acetic acid was ozomzed at 0 until thinlayer chromatography did not show any 38 starting material. The reactionmixture was then poured into 100 m1. of water and the mixture was thenheated to 100 for 30 minutes. The mixture was then concentrated in vacuoand treated with 50 ml. of saturated sodium 'bicarbonate solution. .Theundissolved material was extracted with 100 ml. of ether. The extractwas chromatographed on silica gel using methylene chloride. The eluateswere concentrated and gave, on addition of hexane, 11B formyloxy 10$-desA-androstan-S,l7-dione, M.P. 117117.5 (recrystallized fromacetone-cyclohexane), [(X.]D25=93 (dioxane).

EXAMPLE 93 By hydrolysis of 1lfl-formyloxy-10-desA-androstane-5,17-dione in 2% methanolic potassium hydroxide there is obtained1lfl-hydroxy-l0gadesA-androstan-5,17-dione, which melts at 154; +96(dioxane).

EXAMPLE 94 250 mg. of 1lfl-hydroxy-105-desA-androstane-5,17- dione and250 mg. of p-toluene sulfonic acid monohydrate in 20 ml. of benzene wererefluxed in a nitrogen atmosphere for 6 hours. The reaction mixture wasthen washed with an aqueous solution of sodium bicarbonate and then withwater, dried over sodium sulfate, filtered and evaporated to dryness.The residue was then chromatographed over silicagel (5 g.) indichloromethane. Triturating the residue obtained from the first 250 ml.eluted, yielded crystals of desA-androst-9-ene-5,17-dione, which uponrecrystallization from cyclohexane melted at 123-1235".

EXAMPLE 95 The compound, 1lfl-formyloxy-S,17-dioxo-3,5-seco-A-nor-androstan-3-oic acid is prepared from11B-formyloxyandrost-4-ene-3,17-dione by ozonolysis according to theprocedure of Example 11. The so-obtained product melts at 220-221"; [u]+107 (dioxane).

EXAMPLE 96 3.7 g. of the sodium salt of 11Bformyloxy-5,17-dioxo-3,5-seco-A-nor-androstan-B-oic acid and 12 g. of sodium phenylacetateare fused together in vacuo (0.1 torr). When the bath temperaturereaches 220 the molten mass begins to decompose. The bath is then heatedfurther (within 30 minutes) to a temperature of 290. Once thistemperature has been reached the mixture is left for another 10 minutesat the initial pressure of 0.1 torr. The distilled material is thenchromatographed over 30 g. of aluminum oxide (activity grade 3). Elutionwith a total of 200 ml. of petroleum ether-benzene (2:1), followed byevaporation of the solvent and trituration of the residue in thepresence of petroleum ether, yields desA- androst-9-ene-5,17-dione whichupon recrystallization from cyclohexnae melts at 123-123.5; [a] =-|83(c.=0.1021, dioxane).

EXAMPLE 97 ZOB-acetoxy-5-oxo-3,S-seco-A-nor-pregnan-3-oic acid isprepared by ozonolysis of 20B-acetoxy-pregn-4-en-3-one according to theprocedure of Exmaple 1.

EXAMPLE 98 A solution of 15.15 g. of ZOBacetoxy-S-oxo-B,S-seco-A-nor-pregnan-3-oic acid in 250 ml. of 75% methanol containing 10 g. ofpotassium hydroxide was refluxed for 2 hours. The methanol was thenremoved in vacuo and the residue was dissolved in 100 ml. of water. Thesolution was chilled to 0 and acidified to congo red by the addition of20% hydrochloric acid. There was thus obtained 20Bhydroxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid, M.P. 181-182", [a] =13(dioxane).

A solution of 4.7 g. of 20t3-hydroxy-5-oxo 3,5-seco- A-nor-pregnan-3-oicacid in 100 ml. of methanol was neutralized with 1 N sodium methylatesolution against phenolphthaleine The solution was then evaporated andthe residue, consisting of 20,6-hydroxy-5-oxo-3,5-seco-A-nor-pregnan-B-oic acid sodium salt, was refluxed with 100 m1. ofquinoline for 8 hours. The cooled mixture was poured on a mixture of 150g. of ice and 100 ml. concentrated hydrochloric acid and extracted withether. The ether extract was worked up and the oily residue waschromatographed on silica gel. Elution with methylene chloride gave10a-desA-pregnane-S,20-dione, M.P. 126-127" (crystallized from isopropylether), [a] =82 (dioxane). Elution with methylene chloride containing 1%acetone gave 20;8-hydroxy-10a-desA-pregnan-5-one, M.P. 104-1045(crystallized from ether-hexane) (dioxane). The fractions obtained withmethylene chloride containing -10% acetone were evaporated and the oilyresidue was dissolved in 40 ml. of acetone. The solution was treatedwith 2 ml. of Jones reagent (0.004 mole CrO at and kept at the sametemperature for 10 minutes. After the addition of 5 ml. of methanol, thesolution was evaporated and the residue was diluted with water andextracted with ether. The ether extract was worked up and gave10a-desA-pregnane-5,20-dione.

EXAMPLE 99 20fl-hydroxy-desA-pregn-9-en-5-one is preferred fromZOB-hydroxy-lOa-desA-pregnan-S-one by bromination followed bydehydrobromination, according to the precedure of Example 3. Theso-obtained product, after recrystallization from methylenechloride-petroleum ether, melts at 122-123.

EXAMPLE 100 5,20-dioxo-3,5seco-A-nor-pregnan-3-oic added is prepared byozonolysis of progesterone according to the procedure of Example 1.

EXAMPLE 1 0 l 10a-desA-pregna-5,20-dione and IOB-desA-pregnan-S,20-dione are prepared from 5,20-dioxo-3,5-seco-A-norpregnan-3-oic acidby conversion of the latter to its sodium salt followed by pyrolysis,according to the procedure of Example 2.

EXAMPLE 102 The compound, desA-pregn-9-ene-5,20-dione is prepared from10a-desA-pregna-5,20-dione by bromination followed by dehydrobrominationaccording to the procedure of Example 3. The soobtained product, afterrecrystallization from ether, melts at 111-113 EXAMPLE 103 ml. of 0.8%potassium permanganate solution was added to a mixture of 11 g. offi-tetrahydropyranyloxypregn-4-ene-3-one, 500 m1. of an azeotropicmixture of tertiary butanol and water, 7 g. of potassium carbonate, 20ml. of water and 120 ml. of 7% sodium metaperiodate solution withvigorous stirring at room temperature. 250 m1. of 7% sodiummetaperiodate and 20 ml. of 0.8% potassium permanganate solution werethen simultaneously added within 15 minutes. To the so-obtainedsuspension, 220 ml. of 7% sodium metaperiodate solution and, in order tokeep the mixture violet in color, 15 ml. of 0.8% potassium permanganatesolution was then added in the course of 30 minutes. The mixture wasthen stirred for 90 minutes, filtered over a filter aid (Hyflo) and theresidue was washed with 100 ml. of -tert.butanol-Water azotrope. Thefiltrate was evaporated in vacuo at 50 and the residue diluted with 150ml. of water. The solution was acidified with cold 20% hydrochloric acidto congo red, and the resultant oily material taken up in 150 ml. ofmethylene chloride. The organic extract was washed with water, dried andevaporated and the residue wase purified by filtration over silica gelusing methylene chloride and methylene chloride containing l2% ethanolas the elution agents. There was thus obtainedZOfi-tetrahydropyranyloxy-S-oxo 3,5 seco-A-nor-pregnan-3-oic acid as avis- C0118 oil.

40 EXAMPLE 104 To a solution of 35.8 g. of a mixture of 20w and20phydroxy-pregnl-en-3-one in 500 ml. of anhydrous benzene, there wereadded 75 ml. of 1% p-toluenesulfonic acid in benzene and then 35 ml. ofdihydropyran. The reaction mixture was allowed to stand at roomtemperature for 16 hours, washed with 2% aqueous sodium bicarbonate andwater, dried and concentrated in vacuo at 11 mm. Hg and The residueconsisting of 20(1- and 20B-tetrahydropyranyloxy-pregn-4-en-3-one wasdissolved in 2 liters of tert. butanol-water azeotrope followed by theaddition of a solution of 33 g. of potassium carbonate in 80 m1. ofwater and 620 ml. of 7% aqueous sodium metaperiodate solution. To thereaction mixture there was first added with vigorous stirring at roomtemperature, 75 ml. of 0.8% potassium permanganate and thereaftersimultaneously within 30 minutes 1350 ml. of 7% sodium metaperiodatesolution and ml. of 0.8% potassium permanganate solution. Another 1080ml. of 7% sodium metaperiodate solution and 100 ml. of 0.8% potassiumpermanganate solution were then added within 45 minutes. The reactionmixture was then stirred for 1 hour, filtered over a filter aid (Hyflo)and the residue was washed with 250 ml. of tert. butanol-waterazeotrope. The filterate was evaporated, the residue taken up in 800 ml.of water and filtered. The alkaline filtrate was chilled to 0, acidifiedwith cold 20% hydrochloric acid and extracted with methylene chloride.After working up, the extract afforded a mixture of 200:- and20,8-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid as aviscous oil. This oil was dissolved in 300 ml. of methanol andneutralized with 1 N lithium methylate. The solution was evaporated todryness in vacuo. The oily residue was dissolved in 300 ml. of benzene,evaporated again and dried at 11 mm. Hg and 100 for 2 hours. There wasobtained a mixture of the lithium salts of 2011- and 20,8-tetrahydropyranyloxy-S-oxo 3,5 seco-A-nor-pregnan-S- oic acid as anamorphous powder.

EXAMPLE A solution of 9 g. of 20;8-tetrahydropyranyloxy-S-oxo-3,5-seco-A-nor-pregnan-3-oic acid in 100 ml. of methanol was neutralizedwith 1 N lithium methylation against phenolphthaleine, followed byevaporation in vacuo to dryness. The so-obtained residue was taken up inbenzene, and the benzene evaporated yieldingZOB-tetrahydropyranyloxy-5-oxo-3,5 seco-A-nor-pregnan-3-oic acid lithiumsalt as a semi-crystalline powder.

5 g. of this lithium salt, 7.5 g. of anhydrous sodium acetate and 7.5 g.of anhydrous potassium acetate were mixed and pyrolyzed at 0.02 to 0.1mm. Hg and 290 for 4 hours. The distillate was chromatographed on silicagel using methylene chloride and methylene chloride containing 0.51%acetone as the elution agents. The fractions were evaporated and gave ontreatment with etherhexane 2013-tetrahydropyranyloxy IOa-desA pregnan-S-one, M.P. 125.5-127 (crystallized from methanol) [a] =53 (dioxane).

The oily part of the evaporation residue containing besides the lattercompound the compound ZOfl-tetrahydropyranyloxy-lOB-desA-pregnan-S-one.After the addition of 10 ml. of water and 200 mg. of p-toluenesulfonicacid monohydrate, the solution was refluxed for 60 minutes andevaporated in vacuo. The residue was then treated with water andextracted with ether. The ether extract was worked up and gave20;.8-hydroxy-10a-desA-pregnan- 5-one, M.P. 104.5-105 (crystallized fromether-hexane).

EXAMPLE 106 250 mg. of ZOB-tetrahydropyranyloxy-IOa-desA-pregnan-5-onewas dissolved in 8 ml. of ethanol and after the addition of 1 ml. ofwater and 15 mg. 'of p-t oluenesulfonic acid monohydrate refluxed for 1hour. The reaction mixture was then evaporated and the residue taken upin ether. The ether extract was worked up and gave 205-

